Stress-level glucocorticoids increase fasting hunger and decrease cerebral blood flow in regions regulating eating.

CONTEXT: The neural regulation of appetite and energy homeostasis significantly overlaps with the neurobiology of stress. Frequent exposure to repeated acute stressors may cause increased allostatic load and subsequent dysregulation of the cortico-limbic striatal system leading to inefficient integration of postprandial homeostatic and hedonic signals. It is therefore important to understand the neural mechanisms by which stress generates alterations in appetite that may drive weight gain. OBJECTIVE: To determine glucocorticoid effects on metabolic, neural and behavioral factors that may underlie the association between glucocorticoids, appetite and obesity risk. METHODS: A randomized double-blind cross-over design of overnight infusion of hydrocortisone or saline followed by a fasting morning perfusion magnetic resonance imaging to assess regional cerebral blood flow (CBF) was completed. Visual Analog Scale (VAS) hunger, cortisol and metabolic hormones were also measured. RESULTS: Hydrocortisone relative to saline significantly decreased whole brain voxel based CBF responses in the hypothalamus and related cortico-striatal-limbic regions. Hydrocortisone significantly increased hunger VAS pre-scan, insulin, glucose and leptin, but not other metabolic hormones versus saline CBF groups. Hydrocortisone related increases in hunger were predicted by less reduction of CBF (hydrocortisone minus saline) in the medial OFC, medial brainstem and thalamus, left primary sensory cortex and right superior and medial temporal gyrus. Hunger ratings were also positively associated with plasma insulin on hydrocortisone but not saline day. CONCLUSIONS: Increased glucocorticoids at levels akin to those experienced during psychological stress, result in increased fasting hunger and decreased regional cerebral blood flow in a distinct brain network of prefrontal, emotional, reward, motivation, sensory and homeostatic regions that underlie control of food intake.

Characterizing the Effects of Diabetes and Obesity on Insulin and Leptin Levels amongst Pregnant Women.

OBJECTIVE: In this study, we assess the impact of obesity and diabetes on maternal brain and periphery, as well as fetal exposure to insulin and leptin, and two hormones that play an important role in regulating energy homeostasis. STUDY DESIGN: Fasting maternal plasma, fetal cord vein and artery plasma, and maternal cerebrospinal fluid (CSF) were collected in 37 women (12 lean, nondiabetic [prepregnancy body mass index (BMI): 22.9 ± 1.7 kg/m2]; 12 overweight/obese nondiabetic [BMI: 37.8 ± 7.3 kg/m2]; 13 gestational/type 2 diabetes mellitus [BMI: 29.8 ± 7.3 kg/m2]) with uncomplicated singleton pregnancies undergoing elective Cesarean delivery. HbA1C, insulin, glucose, and leptin levels were measured. RESULTS: Compared with lean mothers, mothers with obesity and diabetes mellitus (DM) had significantly lower CSF-to-plasma ratios of insulin. Moreover, mothers with obesity and DM had significantly lower cord arterial and cord venous to maternal plasma ratios of insulin, but not leptin, compared with lean mothers. There were no differences in CSF and cord blood insulin and leptin levels between obese and DM mothers. CONCLUSION: Compared with lean individuals, mothers with obesity and DM have relative deficiencies in insulin exposure. The patterns observed in mothers with obesity and diabetes were similar highlighting the importance of the maternal metabolic environment in obesity and suggesting obese patients warrant further clinical focus.

Differential Resting State Connectivity Responses to Glycemic State in Type 1 Diabetes.

CONTEXT: Individuals with type 1 diabetes mellitus (T1DM) have alterations in brain activity that have been postulated to contribute to the adverse neurocognitive consequences of T1DM; however, the impact of T1DM and hypoglycemic unawareness on the brain's resting state activity remains unclear. OBJECTIVE: To determine whether individuals with T1DM and hypoglycemia unawareness (T1DM-Unaware) had changes in the brain resting state functional connectivity compared to healthy controls (HC) and those with T1DM and hypoglycemia awareness (T1DM-Aware). DESIGN: Observational study. SETTING: Academic medical center. PARTICIPANTS: 27 individuals with T1DM and 12 HC volunteers participated in the study. INTERVENTION: All participants underwent blood oxygenation level dependent (BOLD) resting state functional magnetic brain imaging during a 2-step hyperinsulinemic euglycemic (90 mg/dL)-hypoglycemic (60 mg/dL) clamp. OUTCOME: Changes in resting state functional connectivity. RESULTS: Using 2 separate methods of functional connectivity analysis, we identified distinct differences in the resting state brain responses to mild hypoglycemia between HC, T1DM-Aware, and T1DM-Unaware participants, particularly in the angular gyrus, an integral component of the default mode network (DMN). Furthermore, changes in angular gyrus connectivity also correlated with greater symptoms of hypoglycemia (r = 0.461, P = 0.003) as well as higher scores of perceived stress (r = 0.531, P = 0.016). CONCLUSION: These findings provide evidence that individuals with T1DM have changes in the brain's resting state connectivity patterns, which may be further associated with differences in awareness to hypoglycemia. These changes in connectivity may be associated with alterations in functional outcomes among individuals with T1DM.

In a Free-Living Setting, Obesity Is Associated With Greater Food Intake in Response to a Similar Premeal Glucose Nadir.

PURPOSE: Changes in blood glucose levels have been shown to influence eating in healthy individuals; however, less is known about effects of glucose on food intake in individuals who are obese (OB). The goal of this study was to determine the predictive effect of circulating glucose levels on eating in free-living OB and normal weight (NW) individuals. METHODS: Interstitial glucose levels, measured with a continuous glucose monitor (CGM) system, were obtained from 15 OB and 16 NW volunteers (age: 40 ± 14 and 37 ± 12 years; weight: 91 ± 13 and 68 ± 12 kg; hemoglobin A1c: 5.1% ± 0.7% and 5.2% ± 0.4%, respectively). While wearing the CGM, participants filled out a food log (mealtime, hunger rating, and amount of food). Glucose profiles were measured in relation to their meals [macro program (CGM peak and nadir analysis) using Microsoft® Excel]. RESULTS: OB and NW individuals showed comparable CGM glucose levels: mean [OB = 100 ± 8 mg/dL; NW = 99 ± 13 mg/dL; P = nonsignificant (NS)] and SD (OB = 18 ± 5 mg/dL, NW = 18 ± 4 mg/dL; P = NS). Obesity was associated with slower postprandial rate of changing glucose levels (P = 0.04). Preprandial nadir glucose levels predicted hunger and food intake in both groups (P < 0.0001), although hunger was associated with greater food intake in OB individuals than in NW individuals (P = 0.008 for group interaction). CONCLUSIONS: Premeal glucose nadir predicted hunger and food intake in a group of free-living, healthy, nondiabetic NW and OB individuals; however for a similar low glucose level stimulus, hunger-induced food intake was greater in OB than NW individuals.

Hypoglycemia unawareness in type 1 diabetes suppresses brain responses to hypoglycemia.

BACKGROUND: Among nondiabetic individuals, mild glucose decrements alter brain activity in regions linked to reward, motivation, and executive control. Whether these effects differ in type 1 diabetes mellitus (T1DM) patients with and without hypoglycemia awareness remains unclear. METHODS: Forty-two individuals (13 healthy control [HC] subjects, 16 T1DM individuals with hypoglycemia awareness [T1DM-Aware], and 13 T1DM individuals with hypoglycemia unawareness [T1DM-Unaware]) underwent blood oxygen level-dependent functional MRI brain imaging during a 2-step hyperinsulinemic euglycemic (90 mg/dl)-hypoglycemic (60 mg/dl) clamp for assessment of neural responses to mild hypoglycemia. RESULTS: Mild hypoglycemia in HC subjects altered activity in the caudate, insula, prefrontal cortex, and angular gyrus, whereas T1DM-Aware subjects showed no caudate and insula changes, but showed altered activation patterns in the prefrontal cortex and angular gyrus. Most strikingly, in direct contrast to HC and T1DM-Aware subjects, T1DM-Unaware subjects failed to show any hypoglycemia-induced changes in brain activity. These findings were also associated with blunted hormonal counterregulatory responses and hypoglycemia symptom scores during mild hypoglycemia. CONCLUSION: In T1DM, and in particular T1DM-Unaware patients, there is a progressive blunting of brain responses in cortico-striatal and fronto-parietal neurocircuits in response to mild-moderate hypoglycemia. These findings have implications for understanding why individuals with impaired hypoglycemia awareness fail to respond appropriately to falling blood glucose levels. FUNDING: This study was supported in part by NIH grants R01DK020495, P30 DK045735, K23DK109284, K08AA023545. The Yale Center for Clinical Investigation is supported by an NIH Clinical Translational Science Award (UL1 RR024139).

Blunted rise in brain glucose levels during hyperglycemia in adults with obesity and T2DM.

In rodent models, obesity and hyperglycemia alter cerebral glucose metabolism and glucose transport into the brain, resulting in disordered cerebral function as well as inappropriate responses to homeostatic and hedonic inputs. Whether similar findings are seen in the human brain remains unclear. In this study, 25 participants (9 healthy participants; 10 obese nondiabetic participants; and 6 poorly controlled, insulin- and metformin-treated type 2 diabetes mellitus (T2DM) participants) underwent 1H magnetic resonance spectroscopy scanning in the occipital lobe to measure the change in intracerebral glucose levels during a 2-hour hyperglycemic clamp (glucose ~220 mg/dl). The change in intracerebral glucose was significantly different across groups after controlling for age and sex, despite similar plasma glucose levels at baseline and during hyperglycemia. Compared with lean participants, brain glucose increments were lower in participants with obesity and T2DM. Furthermore, the change in brain glucose correlated inversely with plasma free fatty acid (FFA) levels during hyperglycemia. These data suggest that obesity and poorly controlled T2DM progressively diminish brain glucose responses to hyperglycemia, which has important implications for understanding not only the altered feeding behavior, but also the adverse neurocognitive consequences associated with obesity and T2DM.