[Show abstract][Hide abstract] ABSTRACT: Type 2 diabetes mellitus (T2DM) is characterized by obesity, hyperglycemia and insulin resistance. Both T2DM and obesity are associated with cerebral complications, including an increased risk of cognitive impairment and dementia, however the underlying mechanisms are largely unknown. In the current study, we aimed to determine the relative contributions of obesity and the presence of T2DM to altered white matter structure. We used diffusion tensor imaging (DTI) and voxel-based morphometry (VBM) to measure white matter integrity and volume in obese T2DM patients without micro- or macrovascular complications, age- gender- and BMI-matched normoglycemic obese subjects and age- and gender-matched normoglycemic lean subjects. We found that obese T2DM patients compared with lean subjects had lower axial diffusivity (in the right corticospinal tract, right inferior fronto-occipital tract, right superior longitudinal fasciculus and right forceps major) and reduced white matter volume (in the right inferior parietal lobe and the left external capsule region). In normoglycemic obese compared with lean subjects axial diffusivity as well as white matter volume tended to be reduced, whereas there were no significant differences between normoglycemic obese subjects and T2DM patients. Decreased white matter integrity and volume were univariately related to higher age, being male, higher BMI, HbA1C and fasting glucose and insulin levels. However, multivariate analyses demonstrated that only BMI was independently related to white matter integrity, and age, gender and BMI to white matter volume loss. Our data indicate that obese T2DM patients have reduced white matter integrity and volume, but that this is largely explained by BMI, rather than T2DM per se.
Full-text · Article · Jan 2016 · Metabolic Brain Disease
[Show abstract][Hide abstract] ABSTRACT: Glucagon-like peptide-1 (GLP-1) affects appetite, supposedly mediated via the central nervous system (CNS). We investigate if modulation of CNS responses to palatable food consumption may be a mechanism by which GLP-1 contributes to the central regulation of feeding. Using functional-MRI, we determined effects of endogenous GLP-1 and treatment with the GLP-1 analogue liraglutide on CNS activation to chocolate milk receipt. Study 1 included 20 healthy lean individuals and 20 obese patients with type 2 diabetes (T2DM). Scans were performed on two occasions: during infusion of the GLP-1 receptor antagonist exendin9-39 (blocking actions of endogenous GLP-1), and during placebo infusion. Study 2 was a randomised, cross-over intervention study in 20 T2DM patients, comparing treatment with liraglutide to insulin, after 10-days and 12-weeks. Compared to lean individuals, T2DM patients showed reduced activation to chocolate milk in right insula (P=0.04). In lean individuals, blockade of endogenous GLP-1 effects inhibited activation in bilateral insula (P≤0.03). Treatment in T2DM with liraglutide, vs. insulin, increased activation to chocolate milk in right insula and caudate nucleus after 10 days (P≤0.03), but these effect ceased to be significant after 12-weeks. Our findings in healthy lean individuals indicate that endogenous GLP-1 is involved in the central regulation of feeding by affecting central responsiveness to palatable food consumption. In obese T2DM, treatment with liraglutide may improve the observed deficit in responsiveness to palatable food, which may contribute to the induction of weight loss observed during treatment. However, no long-term effects of liraglutide were observed.
No preview · Article · Jan 2016 · Journal of Endocrinology
[Show abstract][Hide abstract] ABSTRACT: Context:
Glucagon-like peptide-1 (GLP-1) and GLP-1receptor agonist treatment in type 2 diabetes (T2DM) reduce blood glucose and food intake. It has been suggested that these effects are partly mediated through central GLP-1receptors (GLP-1R). The rodent and nonhuman primate hypothalamus show clear GLP-1R expression. However, a detailed description of GLP-1R expression in the human hypothalamus is lacking, and it is unknown whether this expression is altered in T2DM patients.
To investigate the GLP-1R distribution in the human post-mortem hypothalamus and to determine if hypothalamic GLP-1R expression is altered in T2DM patients.
We investigated the distribution of GLP-1R expression throughout the human hypothalamus by means of in situ hybridization. We also performed quantifications of GLP-1R mRNA expression in two hypothalamic nuclei (i.e. the paraventricular nucleus (PVN) and infundibular nucleus (IFN)), comparing patients with T2DM and control subjects.
We found that GLP-1R mRNA was expressed in a number of hypothalamic nuclei including the PVN and the IFN, both involved in the regulation of energy metabolism. We observed sporadic co-localization of the GLP-1R in the IFN with the orgexigenic neuropeptide Y (NPY), agouti related peptide (AGRP), or pro-opiomelanocortin (POMC) transcripts. Comparison of GLP-1R mRNA in the PVN and IFN between T2DM patients and control subjects revealed a decreased expression in T2DM patients.
Our studies show that GLP-1R is widely expressed throughout the human hypothalamus. The decreased expression of GLP-1R in the PVN and IFN of T2DM patients may be related to dysregulation of feeding behavior and glucose homeostasis in T2DM.
Full-text · Article · Dec 2015 · The Journal of Clinical Endocrinology and Metabolism
[Show abstract][Hide abstract] ABSTRACT: Type 1 diabetes mellitus (T1DM) is associated with microangiopathy and a twofold increased risk of major depressive disorder. Cerebral compromise, which is mostly seen in patients with microangiopathy, may be exacerbated by the presence of clinically relevant depressive symptoms (CRDS).
[Show abstract][Hide abstract] ABSTRACT: Intensive insulin therapy improves the long-term outcome of diabetes patients, but is also associated with weight gain. Insulin detemir (ID) is a relatively new basal insulin analogue, which has consistently been shown to result in less weight gain as compared to other insulin therapies. Since insulin enters the brain, stimulates cerebral glucose metabolism and acts centrally as a satiety signal, differential effects of insulin therapies in the brain could possibly account for these reported differences in weight gain. Cerebral glucose metabolism (cerebral metabolic rate of glucose, CMRglu) can be measured using [18F]-fluoro- 2-deoxy-D-glucose ([18F]FDG) and positron emission tomography (PET).
[Show abstract][Hide abstract] ABSTRACT: Type 1 diabetes (T1DM) is associated with cognitive changes predominantly found in domains concerning information processing speed indicative of white matter involvement. White matter hyperintensities, however, have previously not been found more prevalent in T1DM compared to controls not related to cognitive functions. Therefore, we assessed white matter tract integrity using Diffusion Tensor Imaging (DTI) and cognitive functions in T1DM patients with and without microangiopathy and controls.
[Show abstract][Hide abstract] ABSTRACT: The GLP-1 receptor agonist (GLP-1RA) exenatide improves glycaemic control and promotes satiety, leading to reductions in food intake and body weight. GLP-1RA actions on the brain may partly mediate satiety and weight effects. We hypothesised that exenatide reduces food intake by affecting CNS reward and satiety circuits.
[Show abstract][Hide abstract] ABSTRACT: Cross-sectional studies showed cognitive and structural brain changes in type 1 diabetes (T1DM) patients, predominantly in those with peripheral microangiopathy. Whether these brain changes progress over time is not well known.
[Show abstract][Hide abstract] ABSTRACT: Small vessel disease (SVD) accounts for most of the strokes in type 1 diabetes mellitus (T1DM). Retinal microvascular changes appear to reflect cerebral SVD, but whether diabetic proliferative retinopathy (PDR) is associated with cerebral SVD is unknown. Moreover, it is unclear whether SVD is limited to the brain or part of a generalized microvascular disorder.
[Show abstract][Hide abstract] ABSTRACT: Normal cognitive functioning depends on intact connectivity, i.e. communication, within brain networks. This can now be assessed during rest with functional magnetic resonance imaging (fMRI). Examples of such networks are default mode, sensorimotor, visual, attention, auditory and language, and working memory networks. In type 1 diabetes (T1DM) reduced mental efficiency is common, particularly if microangiopathy is present. We tested the hypothesis that cognitive decrements are associated with alterations in neural connectivity during rest, and that these network changes vary, depending on degree of microangiopathy.
[Show abstract][Hide abstract] ABSTRACT: Background & aims:
Lower birth weight is associated with an increased risk of cardiovascular and metabolic disease. These associations may, at least in part, be explained by alterations in dietary intake in later life. The aim of this study is to examine whether lower birth weight is associated with alterations in dietary intake in later life, and whether this association is due to intrauterine environmental or genetic factors.
In this observational study birth weight and dietary intake were investigated in 78 dizygotic (DZ) and 94 monozygotic (MZ) adolescent same-sex twin subjects. Birth weight was obtained from the mothers. Dietary intake was assessed by two-day dietary records.
In the total group of twins, lower birth weight was associated with higher intake of saturated fat after adjustment for current weight (1.2 per cent of total energy intake (E%) per kg increase in birth weight, P < 0.01). Intra-pair analysis in all twin pairs demonstrated that twins with the lower birth weight had a 115 kcal higher total energy intake and a 0.7 E% higher saturated fat intake compared to their co-twins with the higher birth weight (P < 0.05). Intra-pair differences in birth weight were negatively associated with differences in energy intake and differences in intake of saturated fat after adjustment for differences in current weight (P = 0.07 and P < 0.05, respectively). Intra-pair differences in birth weight were positively associated with intra-pair differences in intake of dietary fibres (P < 0.05). These intra-pair differences and associations were similar for DZ and MZ twins (P for difference > 0.6).
Lower birth weight was related with higher intake of energy and saturated fat within twin pairs, and these associations were independent of zygosity, suggesting that the association between birth weight and alterations in dietary intake in later life is explained by intrauterine environmental rather than genetic factors.
No preview · Article · Oct 2015 · Clinical Nutrition
[Show abstract][Hide abstract] ABSTRACT: Aims/hypothesis:
The central nervous system (CNS) is a major player in the regulation of food intake. The gut hormone glucagon-like peptide-1 (GLP-1) has been proposed to have an important role in this regulation by relaying information about nutritional status to the CNS. We hypothesised that endogenous GLP-1 has effects on CNS reward and satiety circuits.
This was a randomised, crossover, placebo-controlled intervention study, performed in a university medical centre in the Netherlands. We included patients with type 2 diabetes and healthy lean control subjects. Individuals were eligible if they were 40-65 years. Inclusion criteria for the healthy lean individuals included a BMI <25 kg/m(2) and normoglycaemia. Inclusion criteria for the patients with type 2 diabetes included BMI >26 kg/m(2), HbA1c levels between 42 and 69 mmol/mol (6.0-8.5%) and treatment for diabetes with only oral glucose-lowering agents. We assessed CNS activation, defined as blood oxygen level dependent (BOLD) signal, in response to food pictures in obese patients with type 2 diabetes (n = 20) and healthy lean individuals (n = 20) using functional magnetic resonance imaging (fMRI). fMRI was performed in the fasted state and after meal intake on two occasions, once during infusion of the GLP-1 receptor antagonist exendin 9-39, which was administered to block actions of endogenous GLP-1, and on the other occasion during saline (placebo) infusion. Participants were blinded for the type of infusion. The order of infusion was determined by block randomisation. The primary outcome was the difference in BOLD signal, i.e. in CNS activation, in predefined regions in the CNS in response to viewing food pictures.
All patients were included in the analyses. Patients with type 2 diabetes showed increased CNS activation in CNS areas involved in the regulation of feeding (insula, amygdala and orbitofrontal cortex) in response to food pictures compared with lean individuals (p ≤ 0.04). Meal intake reduced activation in the insula in response to food pictures in both groups (p ≤ 0.05), but this was more pronounced in patients with type 2 diabetes. Blocking actions of endogenous GLP-1 significantly prevented meal-induced reductions in bilateral insula activation in response to food pictures in patients with type 2 diabetes (p ≤ 0.03).
Our findings support the hypothesis that endogenous GLP-1 is involved in postprandial satiating effects in the CNS of obese patients with type 2 diabetes.
ClinicalTrials.gov NCT 01363609 Funding The study was funded in part by a grant from Novo Nordisk.
[Show abstract][Hide abstract] ABSTRACT: The central nervous system (CNS) is a major player in the regulation of feeding. Gut-derived hormones, such as glucagon- like peptide-1 (GLP-1), may relay information about the nutritional status to the CNS. Treatment with GLP-1 agonists, such as liraglutide, is associated with reduced appetite and weight loss. We hypothesized that these effects are mediated by effects on the CNS. We performed a randomized cross-over study in patients with type 2 diabetes (n = 20, mean ± SD, age 59.3 ± 4.1 yr, BMI 32 ± 4.7 kg/m2). Each individual underwent 2 periods of 12 week treatment with either liraglutide or insulin glargine with a 12 week wash-out period. Using fMRI, we determined the effects of treatment on CNS activation to food vs. nonfood pictures in areas regulating reward when fasted and 30 min. after a standardized meal. FMRI scans were performed at baseline, after 10 days and 12 weeks of treatment. After 12 weeks, the decrease in HbA1c was larger with liraglutide vs. insulin (Δ -0.7% vs. -0.2%, p difference < 0.001). Body weight decreased during liraglutide vs insulin (Δ -3.3 kg vs. +0.8 kg, p difference < 0.001). After 10 days, before weight changes had occurred, patients treated with liraglutide, compared to insulin, showed decreased activation to food pictures in left putamen in the postprandial condition. After 10 days, in comparison with insulin, liraglutide enhanced the reducing effect of the meal intake on CNS activation to food pictures in left putamen and amygdala. These differences between liraglutide and insulin were not observed after 12 weeks. Compared to insulin, liraglutide decreased CNS activations in response to food pictures in reward areas after short term, but not after longer term treatment. Our findings suggest that the GLP-1 mediated altered CNS activation may contribute to the induction of weight loss. However the absence of effects after longer term treatment might explain why weight loss does not proceed after the initial treatment period with liraglutide.
[Show abstract][Hide abstract] ABSTRACT: It has been suggested that obese individuals have increased brain reward system activation while anticipating food intake, which may lead to cravings for food, and decreased reward system activation during actual food consumption, which may induce overeating. Gut-derived hormones, such as glucagon-like peptide-1 (GLP-1), are likely involved in the regulation of food intake. GLP-1receptor agonists, used for type 2 diabetes (T2DM), improve glycaemic control and reduce food intake and body weight. We hypothesised that food intake reduction following GLP-1receptor activation is mediated through brain areas regulating anticipatory and consummatory food reward.
As part of a larger study, we determined the effects of GLP-1receptor activation on brain responses to anticipation and receipt of chocolate milk vs. tasteless solution, using functional MRI. Obese T2DM patients, normoglycaemic obese and lean subjects (n = 48) underwent three functional MRI sessions at separate visits with intravenous infusion of A) the GLP-1receptor agonist exenatide, B) exenatide with prior GLP-1receptor blockade by exendin9-39 or C) placebo; during somatostatin pituitary-pancreatic clamps.
BMI negatively correlated with brain responses to receipt of chocolate milk and positively correlated with anticipation of receipt of chocolate milk in brain areas regulating reward, appetite and motivation. Exenatide vs. placebo increased brain responses to receipt of chocolate milk and decreased anticipation of receipt of chocolate milk, paralleled by reductions in food intake. Exendin9-39 largely prevented these effects.
Our findings demonstrate that GLP-1receptor activation decreases anticipatory food reward, which may reduce cravings for food, and increases consummatory food reward, which may prevent overeating.
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No preview · Article · Jun 2015 · Diabetes Obesity and Metabolism
[Show abstract][Hide abstract] ABSTRACT: Gut-derived hormones, such as glucagon-like peptide-1 (GLP-1), have been proposed to relay information to the brain to regulate appetite. GLP-1 receptor agonists, currently used for the treatment of type 2 diabetes (T2DM), improve glycemic control and stimulate satiety leading to decreases in food intake and bodyweight. We hypothesized that food intake reduction following GLP-1 receptor activation is mediated through appetite- and reward-related brain areas. Obese T2DM patients, normoglycemic obese and lean individuals (n=48) were studied in a randomized, crossover, placebo-controlled trial. Using functional MRI we determined the acute effects of intravenous administration of the GLP-1 receptor agonist exenatide, with or without prior GLP-1 receptor blockade using exendin9-39, on brain responses to food pictures, during a somatostatin pancreatic-pituitary clamp. Obese T2DM patients and normoglycemic obese vs. lean subjects showed increased brain responses to food pictures in appetite- and reward-related brain regions (insula and amygdala). Exenatide vs. placebo decreased food intake and food-related brain responses in T2DM patients and obese subjects (in insula, amygdala, putamen and orbitofrontal cortex). These effects were largely blocked by prior GLP-1 receptor blockade using exendin9-39. Our findings provide novel insights into the mechanisms by which GLP-1 regulates food intake and how GLP-1 receptor agonists cause weight loss.