Gestational diabetes alters the fetal heart rate variability during an oral glucose tolerance test: a fetal magnetocardiography study.

OBJECTIVE: Gestational diabetes mellitus (GDM) potentially harms the child before birth. We previously found GDM to be associated with developmental changes in the central nervous system. We now hypothesise that GDM may also impact on the fetal autonomic nervous system under metabolic stress like an oral glucose tolerance test (OGTT). DESIGN: We measured heart rate variability (HRV) of mothers and fetuses during a three-point OGTT using fetal magnetocardiography (fMCG). SETTING: Measurements were performed in the fMEG Centre in Tübingen. POPULATION: After exclusion of 23 participants, 13 pregnant women with GDM and 36 pregnant women with normal glucose tolerance were examined. METHODS: All women underwent the same examination setting with OGTT during which fMCG was recorded three times. MAIN OUTCOME MEASURE(S): Parameters of heart rate variability were measured. RESULTS: Compared with mothers with normal glucose regulation, mothers with GDM showed increased heart rate but no significant differences of maternal HRV. In contrast, HRV in fetuses of mothers with GDM differed from those in the metabolically healthy group regarding standard deviation normal to normal beat (SDNN) (P = 0.012), low-frequency band (P = 0.008) and high-frequency band (P = 0.031). These HRV parameters exhibit a decrease only in GDM fetuses during the second hour of the OGTT. CONCLUSIONS: These results show an altered response of the fetal autonomic nervous system to metabolic stress in GDM-complicated pregnancies. Hence, disturbances in maternal glucose metabolism might not only impact on the central nervous system of the fetus but may also affect the fetal autonomic nervous system. TWEETABLE ABSTRACT: Metabolic stress reveals a different response of fetal autonomic nervous system in GDM-complicated pregnancies.

Oxytocin's inhibitory effect on food intake is stronger in obese than normal-weight men.

BACKGROUND/OBJECTIVES: Animal studies and pilot experiments in men indicate that the hypothalamic neuropeptide oxytocin limits food intake, and raise the question of its potential to improve metabolic control in obesity. SUBJECTS/METHODS: We compared the effect of central nervous oxytocin administration (24 IU) via the intranasal route on ingestive behaviour and metabolic function in 18 young obese men with the results in a group of 20 normal-weight men. In double-blind, placebo-controlled experiments, ad libitum food intake from a test buffet was examined in fasted subjects 45 min after oxytocin administration, followed by the assessment of postprandial, reward-driven snack intake. Energy expenditure was repeatedly assessed by indirect calorimetry and blood was sampled to determine concentrations of blood glucose and hormones. RESULTS: Oxytocin markedly reduced hunger-driven food intake in the fasted state in obese but not in normal-weight men, and led to a reduction in snack consumption in both groups, whereas energy expenditure remained generally unaffected. Hypothalamic-pituitary-adrenal axis secretion and the postprandial rise in plasma glucose were blunted by oxytocin in both groups. CONCLUSIONS: Oxytocin exerts an acutely inhibitory impact on food intake that is enhanced rather than decreased in obese compared with normal-weight men. This pattern puts it in contrast to other metabolically active neuropeptides and bodes well for clinical applications of oxytocin in the treatment of metabolic disorders.

Association between omentin-1, adiponectin and bone health under consideration of osteoprotegerin as possible mediator.

PURPOSE: Several studies implicated a crosstalk between bone and fat in the pathogenesis of osteoporosis. Few studies indicated an association between adiponectin and omentin-1 on the bone remodeling process and bone mineral density, and suggested osteoprotegerin (OPG) as a mediator of this relationship. However, only limited evidence on this relationship is available in humans. Therefore, this study aimed to investigate the association between omentin-1, adiponectin and broadband ultrasound attenuation (BUA) in peri-/premenopausal and postmenopausal women, and to assess the role of OPG as a possible mediator. METHODS: Data from the German population-based EPIC-Potsdam cohort comprising 637 women were analyzed. Multivariable-adjusted ANCOVA including age, BMI, waist circumference, smoking status, education, physical activity, adiponectin or omentin-1 and hormone use was used to investigate potential relationships between the adipokines and BUA levels. A mediation analysis assessed the mediating effect of OPG on the association of BUA and omentin-1 levels. RESULTS: Peri-/premenopausal women had higher BUA levels (112.5 ± 10.1 dB/MHz), compared to postmenopausal women (106.3 ± 10.0 dB/MHz). In peri-/premenopausal women neither adiponectin nor omentin-1 was significantly associated with BUA. In postmenopausal women, adiponectin was not associated with BUA, but 10 % increase in the omentin-1 concentration was significantly associated with 0.44 dB/MHz lower BUA levels (p = 0.01). Omentin-1 was positively associated with OPG (p = 0.02); however, OPG was not significantly related to BUA (p = 0.62). CONCLUSION: Our study provides evidence for an inverse association between circulating omentin-1 and BUA levels in postmenopausal women. However, the present findings do not support a mediating effect of OPG in the adipose tissue-bone pathway.

[Liver volume, intrahepatic fat and body weight in the course of a lifestyle interventional study: Analysis with quantitative MR-based methods]. / Lebervolumen, Leberfettanteil und Körpergewicht im Verlauf einer Lebensstilinterventionsstudie : Eine Analyse mit quantitativen MR-basierten Methoden.

OBJECTIVES: The aim of this study was to investigate potential associations between changes in liver volume, the amount of intrahepatic lipids (IHL) and body weight during lifestyle interventions. MATERIAL AND METHODS: In a prospective study 150 patients with an increased risk for developing type 2 diabetes mellitus were included who followed a caloric restriction diet for 6 months. In the retrospective analysis 18 women and 9 men (age range 22-71 years) with an average body mass index (BMI) of 32 kg/m(2) were enrolled. The liver volume was determined at the beginning and after 6 months by three-dimensional magnetic resonance imaging (3D-MRI, echo gradient, opposed-phase) and IHLs were quantified by volume-selective MR spectroscopy in single voxel stimulated echo acquisition mode (STEAM). Univariable and multivariable correlation analyses between changes of liver volume (Δliver volume), intrahepatic lipids (ΔIHL) and body weight (ΔBW) were performed. RESULTS: Univariable correlation analysis in the whole study cohort showed associations between ΔIHL and ΔBW (r = 0.69; p < 0.0001), ΔIHL and Δliver volume (r = 0.66; p = 0.0002) as well as ΔBW and Δliver volume (r = 0.5; p = 0.0073). Multivariable correlation analysis revealed that changes of liver volume are primarily determined by changes in IHL independent of changes in body weight (ß = 0.0272; 95% CI: 0.0155-0.034; p < 0.0001). CONCLUSION: Changes of liver volume during lifestyle interventions are independent of changes of body weight primarily determined by changes of IHL. These results show the reversibility of augmented liver volume in steatosis if it is possible to reduce IHLs during lifestyle interventions.

Altered brain activity in severely obese women may recover after Roux-en Y gastric bypass surgery.

OBJECTIVE: Neuroimaging studies have demonstrated alterations in brain activity in obese (OB) subjects that might be causally linked to their disorder. Roux-en Y gastric bypass (RYGB) surgery induces a marked and sustained weight loss and may affect brain activity. The aim of this study was to compare brain activity pattern between severely OB women (n=11), normal-weight women (NW, n=11) and previously severely OB women who had undergone RYGB surgery (RYGB, n=9) on average 3.4±0.8 years (all >1 year) before the experiment. DESIGN: Brain activity was assessed by functional magnetic resonance imaging during a one-back task containing food- and non-food-related pictures and during resting state. Hunger and satiety were repeatedly rated on a visual analog scale during the experiment. RESULTS: As compared with NW and also with RYGB women, OB women showed (1) a higher cerebellar and a lower fusiform gyrus activity during the visual stimulation independently of the picture category, (2) a higher hypothalamic activation during the presentation of low- vs high-caloric food pictures, (3) a higher hippocampal and cerebellar activity during the working memory task and (4) a stronger functional connectivity in frontal regions of the default mode network during resting state. There were no differences in brain activity between the NW and RYGB women, both during picture presentation and during resting state. RYGB women generally rated lower on hunger and higher on satiety, whereas there were no differences in these ratings between the OB and NW women. CONCLUSION: Data provide evidence for an altered brain activity pattern in severely OB women and suggest that RYGB surgery and/or the surgically induced weight loss reverses the obesity-associated alterations.

Body iron stores and risk of type 2 diabetes: results from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study.

AIMS/HYPOTHESIS: The aim of this study was to prospectively examine the association between body iron stores and risk of type 2 diabetes. METHODS: We designed a case-cohort study among 27,548 individuals within the population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study. During 7 years of follow-up, 849 incident cases of type 2 diabetes were identified. Of these, 607 remained for analyses after exclusion of participants with missing data or abnormal glucose levels at baseline. A sub-cohort of 2,500 individuals was randomly selected from the full cohort, comprising 1,969 individuals after applying the same exclusion criteria. RESULTS: After adjustment for age, sex, BMI, waist circumference, sports activity, bicycling, education, occupational activity, smoking habit, alcohol consumption and circulating levels of γ-glutamyltransferase, alanine aminotransferase, fetuin-A, high-sensitivity C-reactive protein, adiponectin, HDL-cholesterol and triacylglycerol, higher serum ferritin concentrations were associated with a higher risk of type 2 diabetes (RR in the highest vs lowest quintile, 1.73; 95% CI 1.15, 2.61; p(trend) = 0.002). No significant association was observed for soluble transferrin receptor (RR 1.33; 95% CI 0.85, 2.09; p(trend) = 0.50). The soluble transferrin receptor-to-ferritin ratio was significantly inversely related to risk (RR 0.61; 95% CI 0.41, 0.91; p(trend) = 0.02). CONCLUSIONS/INTERPRETATION: High ferritin levels are associated with higher risk of type 2 diabetes independently of established diabetes risk factors and a range of diabetes biomarkers whereas soluble transferrin receptor concentrations are not related to risk. These results support the hypothesis that higher iron stores below the level of haemochromatosis are associated with risk of type 2 diabetes.

Exercise-induced albuminuria is associated with perivascular renal sinus fat in individuals at increased risk of type 2 diabetes.

AIMS/HYPOTHESIS: Microalbuminuria represents an established surrogate marker of early diabetic nephropathy and glomerular microangiopathy. Increasing evidence is emerging of a role of perivascular adipose tissue (PVAT) as an important link between obesity, insulin resistance and both macro- and microangiopathy. It is not known whether perivascular renal sinus fat (RSF) has an impact on microalbuminuria in the prediabetic stage. We investigated whether RSF quantified by MRI is associated with microalbuminuria before or after exercise. METHODS: Non-diabetic individuals at increased risk of type 2 diabetes were recruited into the Tübingen Lifestyle Intervention Program (TULIP); 146 participants took part in the analysis. RSF was measured in axial MRI sections at the level of the renal artery. Urine was collected before and after exercise stress testing. RESULTS: Participants (age 47 ± 12 years; mean ± SD) reached a mean exercise load of 176 ± 49 W, with a mean arterial peak pressure (MAPP) of 112 ± 14 mmHg. After adjusting for sex, age, visceral adipose tissue (VAT) and MAPP during exercise, RSF was significantly associated with postexercise albumin/creatinine ratio (ACR; p = 0.006). No association between RSF and baseline BP could be observed after adjusting for confounders (p = 0.26), and there was no association between RSF and baseline ACR either (p = 0.2). CONCLUSIONS: RSF is associated with exercise-induced albuminuria independently of sex, age, VAT and MAPP in a non-diabetic cohort at diabetic risk. We conclude that PVAT in the renal sinus may play a role in the pathogenesis of microalbuminuria.

Nasal insulin changes peripheral insulin sensitivity simultaneously with altered activity in homeostatic and reward-related human brain regions.

AIMS/HYPOTHESIS: Impaired insulin sensitivity is a major factor leading to type 2 diabetes. Animal studies suggest that the brain is involved in the regulation of insulin sensitivity. We investigated whether insulin action in the human brain regulates peripheral insulin sensitivity and examined which brain areas are involved. METHODS: Insulin and placebo were given intranasally. Plasma glucose, insulin and C-peptide were measured in 103 participants at 0, 30 and 60 min. A subgroup (n = 12) was also studied with functional MRI, and blood sampling at 0, 30 and 120 min. For each time-point, the HOMA of insulin resistance (HOMA-IR) was calculated as an inverse estimate of peripheral insulin sensitivity. RESULTS: Plasma insulin increased and subsequently decreased. This excursion was accompanied by slightly decreased plasma glucose, resulting in an initially increased HOMA-IR. At 1 h after insulin spray, the HOMA-IR subsequently decreased and remained lower up to 120 min. An increase in hypothalamic activity was observed, which correlated with the increased HOMA-IR at 30 min post-spray. Activity in the putamen, right insula and orbitofrontal cortex correlated with the decreased HOMA-IR at 120 min post-spray. CONCLUSIONS/INTERPRETATION: Central insulin action in specific brain areas, including the hypothalamus, may time-dependently regulate peripheral insulin sensitivity. This introduces a potential novel mechanism for the regulation of peripheral insulin sensitivity and underlines the importance of cerebral insulin action for the whole organism.

Body adiposity index, body fat content and incidence of type 2 diabetes.

AIMS/HYPOTHESIS: The aim of this study was to compare estimates of body fat content, i.e. body adiposity index (BAI), BMI and waist and hip circumferences, with respect to their ability to predict the percentage of body fat (PBF; confirmed by magnetic resonance tomography) and incident type 2 diabetes. METHODS: Associations between anthropometric measurements and PBF were evaluated in the Tübingen Lifestyle Intervention Program (TULIP; 138 men, 222 women), and between these measurements and incident type 2 diabetes in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study (9,729 men, 15,438 women) and the Cooperative Health Research in the Region of Augsburg (KORA) study (5,573 men, 5,628 women), using correlation and multivariate Cox regression analyses. RESULTS: BMI more strongly correlated with PBF (men: r = 0.81, women: r = 0.84) than BAI (r = 0.68 and 0.81, respectively), while waist circumference among men (r = 0.84) and hip circumference among women (r = 0.88) showed the strongest correlations. BAI overestimated PBF among men (mean difference -3.0%), and this error was dependent on the value of PBF. BAI was more weakly associated with diabetes risk (RRs for 1 SD, EPIC-Potsdam men: 1.62 [95% CI 1.52, 1.72], women: 1.67 [95% CI 1.55, 1.80]; KORA men: 1.62 [95% CI 1.48, 1.78], women: 1.82 [95% CI 1.65, 2.02]) compared with BMI (RRs, EPIC-Potsdam men: 1.95 [95% CI 1.83, 2.09], women 1.88 [95% CI 1.76, 2.02], KORA men 1.75 [95% CI 1.62, 1.89], women 2.00 [95% CI 1.81, 2.22]), while waist circumference showed the strongest associations (RRs: 2.17 [95% CI 2.01, 2.35], 2.33 [95% CI 2.15, 2.53], 1.81 [95% CI 1.66, 1.96] and 2.29 [95% CI 2.05, 2.57] for EPIC-Potsdam men and women and KORA men and women, respectively). CONCLUSIONS/INTERPRETATION: Waist circumference in men and hip circumference in women are better predictors of PBF than BAI and BMI. BAI was not as strong a predictor of diabetes as BMI, while waist circumference was the strongest predictor.

High cerebral insulin sensitivity is associated with loss of body fat during lifestyle intervention.

AIMS/HYPOTHESIS: Loss of weight and body fat are major targets in lifestyle interventions to prevent diabetes. In the brain, insulin modulates eating behaviour and weight control, resulting in a negative energy balance. This study aimed to test whether cerebral insulin sensitivity facilitates reduction of body weight and body fat by lifestyle intervention in humans. METHODS: The study was performed as an additional arm of the TUebingen Lifestyle Intervention Program (TULIP). In 28 non-diabetic individuals (14 female/14 male; mean ± SE age 42 ± 2 years; mean ± SE BMI 29.9 ± 0.8 kg/m²), we measured cerebrocortical insulin sensitivity by using magnetoencephalography before lifestyle intervention. Total and visceral fat were measured by using MRI at baseline and after 9 months and 2 years of lifestyle intervention. RESULTS: Insulin-stimulated cerebrocortical theta activity at baseline correlated with a reduction in total adipose tissue (r = -0.59, p = 0.014) and visceral adipose tissue (r = -0.76, p = 0.001) after 9 months of lifestyle intervention, accompanied by a statistical trend for reduction in body weight change (r = -0.37, p = 0.069). Similar results were obtained after 2 years. CONCLUSIONS/INTERPRETATION: Our results suggest that high insulin sensitivity of the human brain facilitates loss of body weight and body fat during lifestyle intervention.

Visceral obesity modulates the impact of apolipoprotein C3 gene variants on liver fat content.

OBJECTIVE: It has not been solved whether subjects carrying the minor alleles of the -455T>C or -482C>T single nucleotide polymorphisms (SNPs) in the apolipoprotein-C3-gene (APOC3) have an increased risk for developing fatty liver and insulin resistance. We investigated the relationships of the SNPs with hepatic APOC3 expression and hypothesized that visceral obesity may modulate the effects of these SNPs on liver fat and insulin sensitivity (IS). METHODS: APOC3 mRNA expression and triglyceride content were determined in liver biopsies from 50 subjects. In a separate group (N=330) liver fat was measured by (1)H-magnetic resonance spectroscopy. IS was estimated during an oral glucose tolerance test (OGTT) and the euglycemic, hyperinsulinemic clamp (N=222). RESULTS: APOC3 mRNA correlated positively with triglyceride content in liver biopsies (r=0.29, P=0.036). Carriers of the minor alleles (-455C and -482T) tended to have higher hepatic APOC3 mRNA expression (1.80 (0.45-3.56) vs 0.77 (0.40-1.64), P=0.09), but not higher triglyceride content (P=0.76). In 330 subjects the genotype did not correlate with liver fat (P=0.97) or IS (OGTT: P=0.41; clamp: P=0.99). However, a significant interaction of the genotype with waist circumference in determining liver fat was detected (P=0.02) in which minor allele carriers had higher liver fat only in the lowest tertile of waist circumference (P=0.01). In agreement, during a 9-month lifestyle intervention the minor allele carriers of the SNP -482C>T in the lowest tertile also had less decrease in liver fat (P=0.04). CONCLUSIONS: APOC3 mRNA expression is increased in fatty liver and is regulated by SNPs in APOC3. The impact of the APOC3 SNPs on fatty liver is small and depends on visceral obesity.

Glucocorticoid receptor gene polymorphisms are associated with reduced first-phase glucose-stimulated insulin secretion and disposition index in women, but not in men.

AIM: Glucocorticoids are efficacious anti-inflammatory agents, but, in susceptible individuals, these drugs may induce glucose intolerance and diabetes by affecting ß-cell function and insulin sensitivity. We assessed whether polymorphisms in the glucocorticoid receptor gene NR3C1 associate with measures of ß-cell function and insulin sensitivity derived from hyperglycaemic clamps in subjects with normal or impaired glucose tolerance. METHODS: A cross-sectional cohort study was conducted in four academic medical centres in the Netherlands and Germany. Four hundred and forty-nine volunteers (188 men; 261 women) were recruited with normal glucose tolerance (n=261) and impaired glucose tolerance (n=188). From 2-h hyperglycaemic clamps, first- and second-phase glucose-stimulated insulin secretion, as well as insulin sensitivity index and disposition index, were calculated. All participants were genotyped for the functional NR3C1 polymorphisms N363S (rs6195), BclI (rs41423247), ER22/23EK (rs6189/6190), 9ß A/G (rs6198) and ThtIIII (rs10052957). Associations between these polymorphisms and ß-cell function parameters were assessed. RESULTS: In women, but not in men, the N363S polymorphism was associated with reduced disposition index (P=1.06 10(-4) ). Also only in women, the ER22/23EK polymorphism was associated with reduced first-phase glucose-stimulated insulin secretion (P=0.011) and disposition index (P=0.003). The other single-nucleotide polymorphisms were not associated with ß-cell function. Finally, none of the polymorphisms was related to insulin sensitivity. CONCLUSION: The N363S and ER22/23EK polymorphisms of the NR3C1 gene are negatively associated with parameters of ß-cell function in women, but not in men.

Insulin resistant phenotype of polycystic ovary syndrome does not seem to be caused by variation in FTO.

Genetic variation in the FTO gene is associated with increased body weight and reduced insulin sensitivity. We investigated whether genetic variation in FTO is associated with polycystic ovary syndrome (PCOS), a condition also characterized by insulin resistance. Furthermore, we tested whether insulin resistance is specifically associated with genetic variation in FTO in women with PCOS. Sixty-two nondiabetic patients with PCOS defined by the Rotterdam criteria were compared to BMI and age-matched women. Each PCOS case was matched to 2 controls. All participants underwent an oral glucose tolerance test and were genotyped for the single nucleotide polymorphism rs8050136 in the FTO gene. There was no difference in the frequency of FTO genotypes between the PCOS and the non-PCOS groups. In non-PCOS participants, genetic variation in FTO is associated with insulin sensitivity (p=0.03). This association remained significant after adjustment for age and/or BMI (p<= 0.03). In subjects with PCOS, however, FTO did not associate with insulin sensitivity (p=0.67). Genetic variation in FTO does not have an impact on insulin sensitivity in women with PCOS and is therefore not involved in the pathogenesis of the insulin resistant phenotype seen in patients with PCOS.

Impairment of GLP1-induced insulin secretion: role of genetic background, insulin resistance and hyperglycaemia.

One major risk factor of type 2 diabetes is the impairment of glucose-induced insulin secretion which is mediated by the individual genetic background and environmental factors. In addition to impairment of glucose-induced insulin secretion, impaired glucagon-like peptide (GLP)1-induced insulin secretion has been identified to be present in subjects with diabetes and impaired glucose tolerance, but little is known about its fundamental mechanisms. The state of GLP1 resistance is probably an important mechanism explaining the reduced incretin effect observed in type 2 diabetes. In this review, we address methods that can be used for the measurement of insulin secretion in response to GLP1 in humans, and studies showing that specific diabetes risk genes are associated with resistance of the secretory function of the ß-cell in response to GLP1 administration. Furthermore, we discuss other factors that are associated with impaired GLP1-induced insulin secretion, for example, insulin resistance. Finally, we provide evidence that hyperglycaemia per se, the genetic background and their interaction result in the development of GLP1 resistance of the ß-cell. We speculate that the response or the non-response to therapy with GLP1 analogues and/or dipeptidyl peptidase-4 (DPP-IV) inhibitors is critically dependent on GLP1 resistance.

Association of changes in body mass index during earlier adulthood and later adulthood with circulating obesity biomarker concentrations in middle-aged men and women.

AIMS/HYPOTHESIS: The objective of our study was to investigate whether changes in BMI during earlier adulthood are more strongly associated with levels of circulating obesity biomarkers in middle age than are BMI changes during later adulthood. METHODS: The study included 1,612 participants from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study. The associations of BMI changes based on recalled BMI for the age ranges 25-40 years (earlier adulthood) and 40-55 years (later adulthood) with later biomarker levels were compared using a linear model, adjusted for BMI at age 25 years and conventional risk factors. RESULTS: BMI changes during both time periods as well as BMI at age 25 years were significantly associated with circulating levels of adiponectin, γ-glutamyltransferase (GGT), alanine aminotransferase (ALT), high-sensitivity C-reactive protein (hs-CRP) and HDL-cholesterol (HDL-C) in both sexes, and of HbA(1c) in women. However, BMI gain for the age range 25-40 years was significantly more strongly associated with unfavourable levels of adiponectin, hs-CRP, HDL-C and HbA(1c) in men and women, and of GGT and ALT in men (p difference <0.05) than BMI gain for the age range 40-55 years. The percentage change in biomarker levels per unit gain in BMI for the age range 25-40 years ranged from 0.81% (HbA(1c)) to 9.80% (hs-CRP) in men, and from 0.75% (HbA(1c)) to 14.7% (hs-CRP) in women, whereas for the age range 40-55 years, values ranged from -0.15% to 4.82% in men and from 0.25% to 7.06% in women. CONCLUSIONS/INTERPRETATION: The results support the hypothesis that an increase in BMI in earlier adulthood is more strongly associated with unfavourable circulating levels of obesity biomarkers later in life than is an increase in BMI in later adulthood.

Effects of a lifestyle intervention in metabolically benign and malign obesity.

AIMS/HYPOTHESIS: We and others recently characterised metabolically benign or healthy obesity (MHO). In the present study we investigated whether a lifestyle intervention is sufficient to place obese insulin-resistant (OIR) individuals in a position where the possible metabolic consequences are similar to those for MHO individuals. METHODS: A total of 262 non-diabetic individuals participated in a 9 month lifestyle intervention programme. Obese individuals (BMI ≥ 30.0 kg/m(2)) were stratified, based on their insulin sensitivity (IS) estimated from an OGTT, into MHO (IS in the upper quartile, n = 26) and OIR (IS in the lower three quartiles, n = 77). Total body and visceral fat were measured by magnetic resonance (MR) tomography and liver fat by (1)H-MR spectroscopy. RESULTS: During the intervention, visceral fat decreased significantly in both groups (both p ≤ 0.009), whereas total body and liver fat decreased only in the OIR group (p < 0.0001; MHO p = 0.12 for total body fat and p = 0.47 for liver fat). IS improved in the OIR group (p < 0.0001), but remained essentially unchanged in the MHO group (p = 0.30). However, despite the significant increase in the OIR group, IS at follow-up barely exceeded 50% of the IS of the MHO group (OIR 9.30 ± 0.53 arbitrary units [AU]; MHO 16.41 ± 1.05 AU; p < 0.0001). CONCLUSIONS/INTERPRETATION: IS improves during the lifestyle intervention in OIR individuals. However, it does not reach a level where adequate protection from type 2 diabetes and cardiovascular disease is expected. Thus, stratification of obese individuals based on their metabolic phenotype is important to identify those who are likely to need early pharmacological treatment in addition to the lifestyle intervention.

Glucose tolerance, insulin sensitivity and insulin release in European non-diabetic carriers of a polymorphism upstream of CDKN2A and CDKN2B.

AIMS/HYPOTHESIS: The aim of this study was to investigate the association of the rs10811661 polymorphism near the CDKN2B/CDKN2A genes with glucose tolerance, insulin sensitivity and insulin release in three samples of white people with European ancestry. METHODS: Sample 1 comprised 845 non-diabetic offspring of type 2 diabetes patients recruited in five European centres participating in the EUGENE2 study. Samples 2 and 3 comprised, respectively, 864 and 524 Italian non-diabetic participants. All individuals underwent an OGTT. Screening for the rs10811661 polymorphism was performed using a TaqMan allelic discrimination assay. RESULTS: The rs10811661 polymorphism did not show a significant association with age, BMI and insulin sensitivity. Participants carrying the TT genotype showed a significant reduction in insulin release, measured by an OGTT-derived index, compared with carriers of the C allele, in the three samples. When these results were pooled with those of three published studies, and meta-analysed with a random-effects model, the T allele was significantly associated with reduced insulin secretion (-35.09 [95% CI 14.68-55.52], p = 0.0008 for CC+CT vs TT; and -29.45 [95% CI 9.51-49.38], p = 0.0038, for the additive model). In addition, in our three samples, participants carrying the TT genotype exhibited an increased risk for impaired glucose tolerance (IGT) compared with carriers of the C allele (OR 1.55 [95% CI 1.20-1.95] for the meta-analysis of the three samples). CONCLUSIONS/INTERPRETATION: Our data, together with the meta-analysis of previously published studies, show that the rs10811661 polymorphism is associated with impaired insulin release and IGT, suggesting that this variant may contribute to type 2 diabetes by affecting beta cell function.

Acute, short-term hyperinsulinemia increases olfactory threshold in healthy subjects.

OBJECTIVE: Smell plays an important role in feeding behavior. We therefore tested whether insulin as a postprandial signal is involved in the regulation of olfactory function. RESEARCH DESIGN AND METHODS: We assessed olfactory thresholds in eight lean subjects (age: 34 ± 7 years, M/F: 5/3) before and during a 2-h hyperinsulinemic (1 mU kg(-1) min(-1)) euglycemic clamp and in eight lean fasted subjects (age: 36 ± 6 years, M/F: 5/3) without insulin infusion at the same time of the day. To define odor thresholds, standardized 'sniffing sticks' were used. RESULTS: Odor thresholds decreased from 7.8 ± 1.2 to 6.2 ± 1.1 during euglycemic hyperinsulinemia (P=0.0173), representing an increase in odor threshold. In the control group, odor thresholds were 8.3 ± 1.6 and did not change after 120 min of fasting (8.9 ± 2.2, P=0.6). CONCLUSIONS: Increased insulin levels lead to a reduced smelling capacity, potentially reducing the pleasantness of eating. Therefore, insulin action in the olfactory bulb may be involved in the process of satiation and may thus be of interest in the pathogenesis of obesity.

A polymorphism in the gene encoding AdipoR1 affects olfactory recognition.

Polymorphisms in the gene encoding adiponectin receptor 1 (AdipoR1) are associated with insulin resistance, fatty liver, increased risk for type 2 diabetes and cardiovascular disease. AdipoR1 is expressed in the central nervous system and in the olfactory mucosa of mice and humans. We therefore hypothesized that a common polymorphism in AdipoR1 might alter olfactory function. We investigated a group of 222 healthy subjects (male: n = 147, female: n = 75) for olfactory recognition, and genotyped them for the polymorphism rs6666089 in the human AdipoR1 gene. This polymorphism has been previously shown to be associated with insulin resistance. Olfactory recognition was tested using standardized sniffing sticks, and parameters of glucose metabolism and serum adiponectin levels were assessed. We found a significant olfactory impairment in carriers of the AdipoR1 polymorphism rs6666089 (olfactory recognition: GG: 89.4 ± 1.2%, GA: 86.9 ± 1.4%, AA: 77.2 ± 4.8%, additive model, P = 0.0004, adjusted for age). Adiponectin levels had no impact on olfactory recognition. Fasting plasma glucose, fasting plasma insulin, body mass index and HbA1c did not differ between the genotype groups. In conclusion, the presence of a genetic variation in AdipoR1 is associated with decreased olfactory recognition in healthy subjects. Adiponectin signalling may have an important role in olfactory function and regulation of appetite.

Type 2 diabetes mellitus and risk of malignancy: is there a strategy to identify a subphenotype of patients with increased susceptibility to endogenous and exogenous hyperinsulinism?

AIMS: To give an overview on the relationship between diabetes mellitus and increased cancer risk. METHODS: We identified studies evaluating the association between diabetes mellitus, its treatment with insulin and insulin analogues and malignancies, paying special attention to studies on in vitro and in vivo effects of the long-acting analogue insulin glargine. RESULTS: Even although the pathophysiological mechanisms underlying the relationship between elevated cancer risk and Type 2 diabetes mellitus are not completely understood, hyperinsulinaemia in the presence of insulin resistance appears to be a key factor. Because of the mitogenic actions of insulin at high concentrations, hyperinsulinaemia may favour tumorigenesis. In line with this, an insulin-based therapy is associated with an increased cancer risk, whereas an insulin-sensitizing treatment results in a cancer risk reduction. Furthermore, alterations of the insulin receptor profile on tumour cells may contribute to an enhanced susceptibility towards insulin. Studies on the analogue insulin glargine have been controversial. In vitro data pointed to an elevated mitogenicity of insulin glargine, whereas in vivo data did not confirm cancerogenous effects. Moreover, recently published clinical studies on the association of insulin glargine (Lantus®) and cancer suggest that treatment with insulin glargine is not associated with increased cancer risk. CONCLUSIONS: The relationship between elevated cancer risk and Type 2 diabetes mellitus has been shown by numerous epidemiological studies, with endogenous and exogenous hyperinsulinaemia in the presence of insulin resistance as potential underlying pathophysiological mechanisms. Recent clinical studies do not support an increased cancer risk in patients treated with insulin glargine.