Glucose Ingestion Fails to Inhibit Hypothalamic Neuronal Activity in Patients With Type 2 Diabetes

Vidarsdottir, Solrun; Smeets, Paul A.M.; Eichelsheim, Diane L.; Osch, Matthias J.P. van; Viergever, Max A.; Romijn, Johannes A.; Pijl, Hanno

doi:10.2337/db07-0193

Cited by 71 publications

(62 citation statements)

References 21 publications

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“…In contrast, previous studies by Smeets and colleagues [4][5][6] have shown a prolonged decrease in signal in the hypothalamus after oral glucose, continuing for at least 30 min after ingestion. Our data tend to support the results of Smeets and colleagues and contradict the results of Liu and colleagues, in that they show a prolonged rather than shortlived signal decrease after ingestion of glucose.…”

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confidence: 65%

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Functional MRI of the hypothalamic response to an oral glucose load

et al. 2012

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Abbreviations ACTo the Editor: Functional MRI (fMRI) using a blood oxygen level dependent (BOLD) sequence provides a tool to measure the effects of alterations in blood glucose on the patterns and magnitudes of neuronal activation in the human brain [1]. Previous experiments using a glucose load have suggested that it is possible in humans to identify changes in the BOLD signal from areas within the hypothalamus [2-6]; however, the results have been contradictory. This study involved seven healthy participants aged 27-38 years (three female, four male; mean±SD BMI 23.6± 1.3 kg/m 2 ), who gave informed consent. The study was approved by the local research ethics committee. Each participant attended for two studies in random order: one involving ingestion of a glucose load and the other water.After anatomical scans and a 5 min baseline period of fMRI acquisition, participants were either given 75 g glucose diluted with 200 ml water or the same volume of water only. fMRI acquisition continued for a further 25 min after the start of drinking. Blood samples for measurement of plasma glucose were taken 5 min before the start of drinking and 25 min after the start of drinking. There was no difference in mean glucose levels between conditions at baseline, but significantly higher values in the glucose arm at the end of the study (4.41±0.31 mmol/l for the water arm vs 5.36± 0.28 mmol/l for the glucose arm, p00.001).With the use of a six-channel head coil at 1.5 T, fMRI variables were: repetition time04 s (three-shot echo planar imaging, volume acquisition in 12 s); echo time045 ms; 50 sagittal slices; 2 mm slice thickness; 0.2 mm interslice gap; 2×2 mm in-plane resolution. The 30 min fMRI measurement produced a sequence of 150 volume acquisitions, which were aligned to the 80th volume using SPM5 software (Wellcome Trust Centre for Neuroimaging, London, UK).The position of the hypothalamus was identified on a near-midline sagittal slice of the 80th fMRI volume acquisition on the basis of landmarks: the anterior commissure (AC), the optic chiasm (OC) and the mammillary body (MM). The MarsBaR toolbox for SPM5 (available from http://marsbar.sourceforge.net/) was used to specify the overall region of interest (ROI)-a parallelogram with three

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confidence: 65%

“…Previous experiments using a glucose load have suggested that it is possible in humans to identify changes in the BOLD signal from areas within the hypothalamus [2][3][4][5][6]; however, the results have been contradictory.…”

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confidence: 97%

Functional MRI of the hypothalamic response to an oral glucose load

et al. 2012

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“…Functional MRI scans detecting blood oxygen level-dependent signals showed hypothalamic signaling changes in response to glucose infusions (86 -88). These changes were diminished or absent in obese (89) and T2DM subjects (88). In addition, a link between CNS insulin and peripheral glucose metabolism was suggested by studies of intranasal insulin.…”

Section: Evidence From Human Studies Supporting Cns Regulation Of Metmentioning

confidence: 97%

Evidence for Central Regulation of Glucose Metabolism

Carey

Kehlenbrink

Hawkins

2013

Journal of Biological Chemistry

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Evidence for central regulation of glucose homeostasis is accumulating from both animal and human studies. Central nutrient and hormone sensing in the hypothalamus appears to coordinate regulation of whole body metabolism. Central signals activate ATP-sensitive potassium (K ATP ) channels, thereby down-regulating glucose production, likely through vagal efferent signals. Recent human studies are consistent with this hypothesis. The contributions of direct and central inputs to metabolic regulation are likely of comparable magnitude, with somewhat delayed central effects and more rapid peripheral effects. Understanding central regulation of glucose metabolism could promote the development of novel therapeutic approaches for such metabolic conditions as diabetes mellitus.The estimated global prevalence of Type 2 diabetes (T2DM) 2 is 347 million (1). Because glycemic control is achieved in only ϳ40% of patients, additional therapeutic strategies are needed (2). Increased endogenous glucose production (EGP) is the main source of fasting hyperglycemia (3, 4), contributing ϳ80% of diurnal hyperglycemia in T2DM (5). Apart from insulin, there is no treatment targeting basal EGP. Better understanding its regulation would have important therapeutic implications. We will examine the evidence for central sensing of nutritional and hormonal signals in animal models and humans, focusing on CNS regulation of glucose metabolism. Evidence for CNS Nutrient and Hormone Sensing in AnimalsUnlike other organs, the brain is an obligate consumer of glucose (6). Central regulation of EGP would therefore be teleologically advantageous. Since the first demonstration by Claude Bernard (7) that lesions in the floor of the fourth ventricle altered blood glucose levels, the ability of central glucose sensing to regulate peripheral glucose homeostasis has been extensively examined in animal models. There are glucosesensing neurons in many areas of the brain (8), particularly the hypothalamus (9). Specifically, the ventromedial hypothalamus (VMH) and arcuate nucleus (10) integrate hormonal and nutrient signals impacting peripheral metabolism (Fig. 1). Central signals appear to activate hypothalamic ATP-sensitive potassium (K ATP ) channels (9,11,12) composed of an inward rectifier potassium ion channel Kir6.2 subunit and a sulfonylurea receptor (SUR) subunit. Pharmacologic compounds including diazoxide activate and thereby close hypothalamic K ATP channels, whereas sulfonylureas inhibit and thereby open them, ultimately modulating EGP (12).Glucose-Elegant studies in rats showed that direct infusion of D-glucose into the VMH inhibited counterregulatory hormonal responses to systemic hypoglycemia during a hypoglycemic clamp, indicating that VMH glucose sensing is needed for the systemic response to peripheral hypoglycemia (13). VMH infusion of L-lactate, a byproduct of glucose metabolism and an alternate fuel source for neurons in conditions of glucose deficiency, produced similar suppression of the counterregulatory hormonal response to systemic...

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“…Glucose levels can modulate neural firing in the hypothalamus (22), and the presence of diabetes (1,44) as well as hyperglycemia (31) has been found to interfere with hypothalamic signaling. However, since neural signals may be necessary only in the preprandial rise of ghrelin (46), the presence of disrupted neural regulation of satiety is therefore unlikely to explain the absence of a postprandial decline in ghrelin levels in our study.…”

Section: E229mentioning

confidence: 99%

Hyperglycemia abolishes meal-induced satiety by a dysregulation of ghrelin and peptide YY_3–36 in healthy overweight/obese humans

Knudsen

Karstoft

Solomon

2014

American Journal of Physiology-Endocrinology and Metabolism

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Satiety and satiety-regulating gut hormone levels are abnormal in hyperglycemic individuals. We aimed to determine whether these abnormalities are secondary to hyperglycemia. Ten healthy overweight/obese subjects (age: 56 ± 3 yr; BMI: 30.3 ± 1.2 kg/m(2)) received three equicaloric meals at t = 0, 4, and 8 h in the absence (control trial) and presence of experimental hyperglycemia (hyperglycemia trial; 5.4 mM above basal). Circulating levels of glucose, insulin, ghrelin, and peptide YY (PYY)3-36 and visual analog scale ratings of satiety were measured throughout each trial. In the control trial, glucose, insulin, PYY3-36, and the feeling of fullness were increased in the postprandial periods, whereas ghrelin was decreased. In the hyperglycemia trial, in which plasma glucose was increased to 11.2 ± 0.1 mmol/l, postprandial meal responses (AUC: 0-2, 4-6, and 8-10 h) of PYY3-36 were lower (meal 1, P < 0.0001; meal 2, P < 0.001; meal 3, P < 0.05), whereas insulin (meal 1, P < 0.01; meal 2, P < 0.001; meal 3, P < 0.05) and ghrelin (meal 1, P < 0.05; meal 2, P > 0.05; meal 3, P > 0.05) were higher compared with the control trial. Furthermore, the incremental (Δ0-0.5, 4-4.5, and 8-8.5 h) ghrelin response to the first and third meals was higher in the hyperglycemia trial in contrast to control (Δ: 2.3 ± 8.0, P = 0.05; Δ: 14.4 ± 2.5, P < 0.05). Also, meal-induced fullness was prevented (meal 1, P = 0.06; meal 2, P = 0.01; meal 3, P = 0.08) by experimental hyperglycemia. Furthermore, trends in ghrelin, PYY3-36, and fullness were described by different polynomial functions between the trials. In conclusion, hyperglycemia abolishes meal-induced satiety and dysregulates postprandial responses of the gut hormones PYY3-36 and ghrelin in overweight/obese healthy humans.

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Glucose Ingestion Fails to Inhibit Hypothalamic Neuronal Activity in Patients With Type 2 Diabetes

Cited by 71 publications

References 21 publications

Functional MRI of the hypothalamic response to an oral glucose load

Functional MRI of the hypothalamic response to an oral glucose load

Evidence for Central Regulation of Glucose Metabolism

Hyperglycemia abolishes meal-induced satiety by a dysregulation of ghrelin and peptide YY_3–36 in healthy overweight/obese humans

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Glucose Ingestion Fails to Inhibit Hypothalamic Neuronal Activity in Patients With Type 2 Diabetes

Cited by 71 publications

References 21 publications

Functional MRI of the hypothalamic response to an oral glucose load

Functional MRI of the hypothalamic response to an oral glucose load

Evidence for Central Regulation of Glucose Metabolism

Hyperglycemia abolishes meal-induced satiety by a dysregulation of ghrelin and peptide YY3–36 in healthy overweight/obese humans

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Product

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Hyperglycemia abolishes meal-induced satiety by a dysregulation of ghrelin and peptide YY_3–36 in healthy overweight/obese humans