Cognitive disorder and dementia in type 2 diabetes mellitus

Insulin, a key pleiotropic hormone, regulates metabolism through several signaling pathways in target tissues including skeletal muscle, liver, and brain. In the brain, insulin modulates learning and memory, and impaired insulin signaling is associated with metabolic dysregulation and neurodegenerative diseases. At the receptor level, in aging and Alzheimer’s disease (AD) models, the amount of insulin receptors and their functions are decreased. Clinical and animal model studies suggest that memory improvements are due to changes in insulin levels. Furthermore, diabetes mellitus (DM) and insulin resistance are associated with age-related cognitive decline, increased levels of β-amyloid peptide, phosphorylation of tau protein; oxidative stress, pro-inflammatory cytokine production, and dyslipidemia. Recent evidence shows that deleting brain insulin receptors leads to mild obesity and insulin resistance without influencing brain size and apoptosis development. Conversely, deleting insulin-like growth factor 1 receptor (IGF-1R) affects brain size and development, and contributes to behavior changes. Insulin is synthesized locally in the brain and is released from the neurons. Here, we reviewed proposed pathophysiological hypotheses to explain increased risk of dementia in the presence of DM. Regardless of the exact sequence of events leading to neurodegeneration, there is strong evidence that mitochondrial dysfunction plays a key role in AD and DM. A triple transgenic mouse model of AD showed mitochondrial dysfunction, oxidative stress, and loss of synaptic integrity. These alterations are comparable to those induced in wild-type mice treated with sucrose, which is consistent with the proposal that mitochondrial alterations are associated with DM and contribute to AD development. Alterations in insulin/IGF-1 signaling in DM could lead to mitochondrial dysfunction and low antioxidant capacity of the cell. Thus, insulin/IGF-1 signaling is important for increased neural processing and systemic metabolism, and could be a specific target for therapeutic strategies to decrease alterations associated with age-related cognitive decline.     

Alzheimer’s disease and type 2 diabetes mellitus: Pathophysiologic and pharmacotherapeutics links

At present, Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2DM) are two highly prevalent disorders worldwide, especially among elderly individuals. T2DM appears to be associated with cognitive dysfunction, with a higher risk of developing neurocognitive disorders, including AD. These diseases have been observed to share various pathophysiological mechanisms, including alterations in insulin signaling, defects in glucose transporters (GLUTs), and mitochondrial dysfunctions in the brain. Therefore, the aim of this review is to summarize the current knowledge regarding the molecular mechanisms implicated in the association of these pathologies as well as recent therapeutic alternatives. In this context, the hyperphosphorylation of tau and the formation of neurofibrillary tangles have been associated with the dysfunction of the phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways in the nervous tissues as well as the decrease in the expression of GLUT-1 and GLUT-3 in the different areas of the brain, increase in reactive oxygen species, and production of mitochondrial alterations that occur in T2DM. These findings have contributed to the implementation of overlapping pharmacological interventions based on the use of insulin and antidiabetic drugs, or, more recently, azeliragon, amylin, among others, which have shown possible beneficial effects in diabetic patients diagnosed with AD.     

Resting-state brain functional connectivity is altered in type 2 diabetes

Type 2 diabetes mellitus (T2DM) is a risk factor for Alzheimer disease (AD). Populations at risk for AD show altered brain activity in the default mode network (DMN) before cognitive dysfunction. We evaluated this brain pattern in T2DM patients. We compared T2DM patients (n = 10, age = 56 ± 2.2 years, fasting plasma glucose [FPG] = 8.4 ± 1.3 mmol/L, HbA(1c) = 7.5 ± 0.54%) with nondiabetic age-matched control subjects (n = 11, age = 54 ± 1.8 years, FPG = 4.8 ± 0.2 mmol/L) using resting-state functional magnetic resonance imaging to evaluate functional connectivity strength among DMN regions. We also evaluated hippocampal volume, cognition, and insulin sensitivity by homeostasis model assessment of insulin resistance (HOMA-IR). Control subjects showed stronger correlations versus T2DM patients in the DMN between the seed (posterior cingulate) and bilateral middle temporal gyrus (β = 0.67 vs. 0.43), the right inferior and left medial frontal gyri (β = 0.75 vs. 0.54), and the left thalamus (β = 0.59 vs. 0.37), respectively, with no group differences in cognition or hippocampal size. In T2DM patients, HOMA-IR was inversely correlated with functional connectivity in the right inferior frontal gyrus and precuneus. T2DM patients showed reduced functional connectivity in the DMN compared with control subjects, which was associated with insulin resistance in selected brain regions, but there were no group effects of brain structure or cognition.     

Diabetes mellitus type 2 as an underlying,comorbid or consequent state of mental disorders

Somatic disturbances that occur in parallel with psychiatric diseases are a major challenge in clinical practice. Various factors contribute to the development of mental and somatic disorders. Type 2 diabetes mellitus (T2DM) is a significant health burden worldwide, and the prevalence of diabetes in adults is increasing. The comorbidity of diabetes and mental disorders is very common. By sharing a bidirectional link, both T2DM and mental disorders influence each other in various manners, but the exact mechanisms underlying this link are not yet elucidated. The potential mechanisms of both mental disorders and T2DM are related to immune and inflammatory system dysfunction, oxidative stress, endothelial dysfunction, and metabolic disturbances. Moreover, diabetes is also a risk factor for cognitive dysfunction that can range from subtle diabetes-associated cognitive decline to pre-dementia and dementia. A complex re-lationship between the gut and the brain also represents a new therapeutic approach since gut-brain signalling pathways regulate food intake and hepatic glucose production. The aim of this minireview is to summarize and present the latest data on mutual pathogenic pathways in these disorders, emphasizing their complexity and interweaving. We also focused on the cognitive performances and changes in neurodegenerative disorders. The importance of implementing integrated approaches in treating both of these states is highlighted, along with the need for individual therapeutic strategies.     

Pathophysiology and management of patients with diabetes mellitus in gastrointestinal surgery, with special reference to hepatectomy and pancreaticoduodenectomy]

In the 235 patients with hepatectomy, 111 with pancreaticoduodenectomy (PD) and 547 with gastrectomy for the past 15 years and 5 months, we compared the incidence of postoperative complications between patients with diabetes mellitus (DM) and those without DM, and studied glucose metabolism and management of diabetic patients. DM was most frequently found at 27.7% in hepatectomy, especially 38.7% in cirrhotic patients, followed by 24.3% in PD and only 5.9% in gastrectomy. The incidence of postoperative complications was not different between DM and non-DM after gastrectomy and PD. It was significantly higher in DM than in non-DM after hepatectomy (38.5% vs. 11.8%), although there was no statistically significant difference in the cirrhotic patients with hepatectomy (34.9% vs. 23.5%). The studies on insulin metabolism preoperatively determined by oral glucose tolerance test and postoperative control of DM revealed that diabetic patients with hepatectomy, especially hepatogenous DM, had a significantly reduced insulin uptake in the liver and exogenous insulin resistance to glucose. After PD for diabetic patients, a long-term care of impaired pancreatic exocrine and endocrine functions was considered to be required, especially paying attention to lipid and zinc metabolism.     

Diabetes mellitus with hyperparathyroidism: another indication for parathyroidectomy?

BACKGROUND: Patients with hyperparathyroidism have alterations in carbohydrate metabolism characterized by insulin resistance, hyperinsulinemia, and glucose intolerance. The clinical significance of these findings in the management of patients with diabetes mellitus (DM) after parathyroidectomy for hyperparathyroidism has been controversial. METHODS: A retrospective review identified 87 patients with DM and hyperparathyroidism who underwent parathyroidectomy. The follow-up documentation of 70 patients who underwent diabetic management was then evaluated to assess the benefit of parathyroidectomy on glucose management. RESULTS: Thirteen patients had type 1 DM, and 74 patients had type 2 DM. Primary hyperparathyroidism was present in 93% of patients with type 2 DM; 64% of patients with type 1 DM had secondary hyperparathyroidism. At follow-up, glucose control was stable in 40% of patients, had improved in 37% of patients, and had deteriorated in 23% of patients (P = .003). Improved glucose control was not dependent on age, duration of DM, duration of hyperparathyroidism, length of follow-up, or calcium levels. The patients with decreased requirements had a significantly lower parathyroid hormone level (P = .05). Improved glucose control was most significant in patients whose condition was managed with oral hypoglycemics (P = .05) or insulin (P = .03). CONCLUSIONS: The clinical and laboratory investigations on the influence of hyperparathyroidism on DM support the benefit of parathyroidectomy in patients with DM. Patients with type 1 and type 2 DM show improvement in glucose control after parathyroidectomy. The presence of DM and hyperparathyroidism is an indication for parathyroidectomy because it results in either stabilization or improved glucose control in 77% of patients.     

Short and long term neuro-behavioral alterations in type 1 diabetes mellitus pediatric population

Type 1 diabetes mellitus(T1DM) is one of the most prevalent chronic conditions affecting individuals under the age of 18 years, with increasing incidence worldwide, especially among very young age groups, younger than 5. There is still no cure for the disease, and therapeutic goals and guidelines are a challenge. Currently, despite T1 DM intensive management and technological interventions in therapy, the majority of pediatric patients do not achieve glycemic control goals. This leads to a potential prognosis of long term diabetic complications, nephrological, cardiac, ophthalmological and neurological. Unfortunately, the neurological manifestations, including neurocognitive and behavioral complications, may present soon after disease onset, during childhood and adolescence. These manifestations may be prominent, but at times subtle, thus they are often not reported by patients or physicians as related to the diabetes. Furthermore, the metabolic mechanism for such manifestations has been inconsistent and difficult to interpret in practical clinical care, as reported in several reviews on the topic of brain and T1 DM. However, new technological methods for brain assessment, as well as the introduction of continuous glucose monitoring, provide new insights and information regarding brain related manifestations and glycemic variability and control parameters, which may impact the clinical care of children and youth with T1 DM. This paper provides a comprehensive review of the most recently reported behavioral, cognitive domains, sleep related, electrophysiological, and structural alterations in children and adolescences from a novel point of view. The review focuses on reported impairments based on duration of T1 DM, its timeline, and modifiable disease related risk parameters. These findings are not without controversy, and limitations of data are presented in addition to recommendations for future research direction.     

Resting-state brain networks in type 1 diabetic patients with and without microangiopathy and their relation to cognitive functions and disease variables

Cognitive functioning depends on intact brain networks that can be assessed with functional magnetic resonance imaging (fMRI) techniques. We hypothesized that cognitive decrements in type 1 diabetes mellitus (T1DM) are associated with alterations in resting-state neural connectivity and that these changes vary according to the degree of microangiopathy. T1DM patients with (MA(+): n = 49) and without (MA(-): n = 52) microangiopathy were compared with 48 healthy control subjects. All completed a neuropsychological assessment and resting-state fMRI. Networks were identified using multisubject independent component analysis; specific group differences within each network were analyzed using the dual-regression method, corrected for confounding factors and multiple comparisons. Relative to control subjects, MA(-) patients showed increased connectivity in networks involved in motor and visual processes, whereas MA(+) patients showed decreased connectivity in networks involving attention, working memory, auditory and language processing, and motor and visual processes. Better information-processing speed and general cognitive ability were related to increased degree of connectivity. T1DM is associated with a functional reorganization of neural networks that varies, dependent on the presence or absence of microangiopathy.     

Molecular and biochemical trajectories from diabetes to Alzheimer's disease: A critical appraisal

Diabetes mellitus(DM), a metabolic disorder is a major orchestra influencing brain and behavioral responses via direct or indirect mechanisms. Many lines of evidence suggest that diabetic patients apparently face severe brain complications, but the story is far from being fully understood. Type 2 diabetes, an ever increasing epidemic and its chronic brain complications are implicated in the development of Alzheimer's disease(AD). Evidences from clinical and experimental studies suggest that insulin draws a clear trajectory from the peripheral system to the central nervous system. This review is a spot light on striking pathological, bio-chemical, molecular and behavioral commonalities of AD and DM. Incidence of cognitive decline in diabetic patients and diabetic symptoms in AD patients has brought the concept of brain diabetes to attention. Brain diabetes reflects insulin resistant brain state with oxidative stress, cognitive impairment, activation of various inflammatory cascade and mitochondrial vulnerability as a shared footprint of AD and DM. It has become extremely important for the investigators to understand the patho-physiology of brain complications in diabetes and put intensive pursuits for therapeutic interventions. Although, decades of research have yielded a range of molecules with potential beneficial effects, but they are yet to meet the expectations.     

Task-Induced Brain Activity Patterns in Type 2 Diabetes: A Potential Biomarker for Cognitive Decline

Patients with type 2 diabetes demonstrate reduced functional connectivity within the resting state default mode network (DMN), which may signal heightened risk for cognitive decline. In other populations at risk for cognitive decline, additional magnetic resonance imaging abnormalities are evident during task performance, including impaired deactivation of the DMN and reduced activation of task-relevant regions. We investigated whether middle-aged type 2 diabetic patients show these brain activity patterns during encoding and recognition tasks. Compared with control participants, we observed both reduced 1) activation of the dorsolateral prefrontal cortex during encoding and 2) deactivation of the DMN during recognition in type 2 diabetic patients, despite normal cognition. During recognition, activation in several task-relevant regions, including the dorsolateral prefrontal cortex and DMN regions, was positively correlated with HbA_1c and insulin resistance, suggesting that these important markers of glucose metabolism impact the brain’s response to a cognitive challenge. Plasma glucose ≥11 mmol/L was associated with impaired deactivation of the DMN, suggesting that acute hyperglycemia contributes to brain abnormalities. Since elderly type 2 diabetic patients often demonstrate cognitive impairments, it is possible that these task-induced brain activity patterns observed in middle age may signal impending cognitive decline.     

糖尿病大鼠逼尿肌线粒体琥珀酸脱氢酶及其超微结构的改变

目的探讨能量代谢与糖尿病膀胱逼尿肌线粒体损伤的关系。方法建立2型糖尿病（T2DM）大鼠模型，在高糖高脂饮食喂养第4、12、24周取大鼠膀胱逼尿肌制备匀浆测定琥珀酸脱氢酶活性。并电镜观测逼尿肌线粒体的形态改变。结果T2DM组大鼠的琥珀酸脱氢酶活性在其发病早期就出现降低；随着T2DM大鼠病程的延长，逼尿肌线粒体超微结构的损伤明显加重。结论在糖尿病膀胱的发病过程中线粒体破坏所导致的逼尿肌能量代谢障碍可能是引起逼尿肌收缩功能障碍的始动因素。     

The challenges of diabetes care in the dialysis unit

Nephrologists, dialysis facilities, and payers are confronted with a new and more difficult set of challenges to effectively care for the steadily increasing number of patients with diabetes mellitus (DM) developing end-stage renal disease (ESRD). U.S. Renal Data System (USRDS) data suggest that the current care of patients with DM on dialysis is suboptimal. Recently published reports have confirmed the value of HbA1C measurements in the diabetic dialysis population, that control of blood glucose lowers mortality, and that a program of care management and diabetes education can have a significant impact on patient outcomes. As leader of the nephrology team, the nephrologist should, at a minimum, be accountable for defining who is managing the diabetes. A more systematic and educated approach to DM and its complications needs to be developed by the renal community.     

Molecular and biochemical trajectories from diabetes to Alzheimer’s disease: A critical appraisal

Diabetes mellitus (DM), a metabolic disorder is a major orchestra influencing brain and behavioral responses via direct or indirect mechanisms. Many lines of evidence suggest that diabetic patients apparently face severe brain complications, but the story is far from being fully understood. Type 2 diabetes, an ever increasing epidemic and its chronic brain complications are implicated in the development of Alzheimer’s disease (AD). Evidences from clinical and experimental studies suggest that insulin draws a clear trajectory from the peripheral system to the central nervous system. This review is a spot light on striking pathological, biochemical, molecular and behavioral commonalities of AD and DM. Incidence of cognitive decline in diabetic patients and diabetic symptoms in AD patients has brought the concept of brain diabetes to attention. Brain diabetes reflects insulin resistant brain state with oxidative stress, cognitive impairment, activation of various inflammatory cascade and mitochondrial vulnerability as a shared footprint of AD and DM. It has become extremely important for the investigators to understand the patho-physiology of brain complications in diabetes and put intensive pursuits for therapeutic interventions. Although, decades of research have yielded a range of molecules with potential beneficial effects, but they are yet to meet the expectations.     

Mechanisms of hypoglycemia unawareness and implications in diabetic patients

Hypoglycemia unawareness(HU) is defined at the onset of neuroglycopenia before the appearance of autonomic warning symptoms.It is a major limitation to achieving tight diabetes and reduced quality of life.HU occurs in approximately 40% of people with type 1 diabetesmellitus(T1DM) and with less frequency in T2 DM.Though the aetiology of HU is multifactorial,possible mechanisms include chronic exposure to low blood glucose,antecedent hypoglycaemia,recurrent severe hypoglycaemia and the failure of counter-regulatory hormones.Clinically it manifests as the inability to recognise impeding hypoglycaemia by symptoms,but the mechanisms and mediators remain largely unknown.Prevention and management of HU is complex,and can only be achieved by a multifactorial intervention of clinical care and structured patient education by the diabetes team.Less know regarding the impact of medications on the development or recognition of this condition in patients with diabetes.Several medications are thought to worsen or promote HU,whereas others may have an attenuating effect on the problem.This article reviews recent advances in how the brain senses and responds to hypoglycaemia,novel mechanisms by which people with insulin-treated diabetes develop HU and impaired counter-regulatory responses.The consequences that HU has on the person with diabetes and their family are also described.Finally,it examines the evidence for prevention and treatment of HU,and summarizes the effects of medications that may influence it.     

β-cell dysfunction: Its critical role in prevention and management of type 2 diabetes

Type 2 diabetes(T2DM) is characterized by insulin resistance and β-cell dysfunction. Although, in contrast to type 1 diabetes, insulin resistance is assumed to be a major pathophysiological feature of T2 DM, T2 DM never develops unless β-cells fail to compensate insulin resistance. Recent studies have revealed that a deficit of β-cell functional mass is an essential component of the pathophysiology of T2 DM, implying that β-cell deficit is a common feature of both type 1 and type 2 diabetes. β-cell dysfunction is present at the diagnosis of T2 DM and progressively worsens with disease duration. β-cell dysfunction is associated with worseningof glycemic control and treatment failure; thus, it is important to preserve or recover β-cell functional mass in the management of T2 DM. Since β-cell regenerative capacity appears somewhat limited in humans, reducing β-cell workload appears to be the most effective way to preserve β-cell functional mass to date, underpinning the importance of lifestyle modification and weight loss for the treatment and prevention of T2 DM. This review summarizes the current knowledge on β-cell functional mass in T2 DM and discusses the treatment strategy for T2 DM.     

Effect of recurrent hypoglycemia on spatial cognition and cognitive metabolism in normal and diabetic rats

The effects of recurrent hypoglycemia (RH) on cognition in human subjects remain controversial, perhaps in part due to difficulty in completely controlling previous hypoglycemic history. We used a model of RH in nondiabetic and diabetic rats to examine the effects of short-term (3 h daily for 3 days) RH on subsequent hippocampally dependent spatial memory, tested either at euglycemia or under acute hypoglycemia. Hippocampal metabolism was simultaneously measured using microdialysis. Antecedent RH improved task performance (79 +/- 2% alternation in nondiabetic RH animals vs. 63 +/- 3% in controls; P < 0.001) at euglycemia, accompanied by reversal of the task-associated dip (20 +/- 1% below baseline) in hippocampal extracellular fluid (ECF) glucose seen in control animals. RH rats also had a larger rise in hippocampal ECF glucose, after intraperitoneal glucose injection, than did controls. However, RH animals tested at acute hypoglycemia ( approximately 2.8 mmol/l) performed significantly worse than control animals. Results were similar in diabetic and nondiabetic rats. Our data suggest that RH causes improvement in subsequent cognitive performance at euglycemia, accompanied by alterations in cognitive metabolism. When glucose availability is limited, complex cognitive functioning seems to be adversely effected in RH animals, perhaps to better maintain and preserve basic brain functions.     

Cognitive performance, psychological well-being, and brain magnetic resonance imaging in older patients with type 1 diabetes

Modest cognitive impairment has been reported in young-adult patients with type 1 diabetes. In older patients with type 2 diabetes, cognitive impairments are more pronounced, which might be due to age but also to differential effects of type 1 diabetes and type 2 diabetes on the brain. This study therefore assessed cognitive performance and magnetic resonance imaging (MRI) of the brain in older type 1 diabetic patients. Forty type 1 diabetic patients (age >50 years) and 40 age-matched control subjects were included. Neuropsychological assessment included all major cognitive domains, and psychological well-being was assessed with questionnaires. Atrophy, white-matter abnormalities, and infarcts were rated on MRI scans. Type 1 diabetic patients performed slightly (effect sizes <0.4) worse on cognitive tasks, but only "speed of information processing" reached statistical significance. No significant between-group differences were found on any of the MRI parameters. Type 1 diabetic patients tended to report more cognitive and depressive problems than control subjects, but this did not correlate with the performance on cognitive tests. We conclude that cognition in older type 1 diabetic patients is only mildly disturbed. Chronic exposure to hyperglycemia is in itself, even at older age, apparently not sufficient to have considerable impact on the brain.     

Alterations in glucose metabolism associated with liver cirrhosis persist in the clinically stable long-term course after liver transplantation.

With increasing long-term survival rates after orthotopic liver transplantation (OLT), metabolic alterations complicating the clinical course, such as diabetes mellitus (DM), become increasingly important. Liver cirrhosis is associated with severe alterations in glucose metabolism. However, it is currently unclear whether these changes are reversed by successful OLT. We therefore characterized glucose metabolism in patients with liver cirrhosis and normal fasting glucose levels before OLT (cir), in the clinically stable long-term course after OLT (OLT), and control subjects (con) using oral glucose tolerance tests (cir = 100, OLT = 62, con = 32), euglycemic-hyperinsulinemic clamps (cir = 10, OLT = 27, con = 14), and positron emission tomography (PET) scan analysis with 18F-fluorodeoxyglucose (FDG) as a tracer (cir = 7, OLT = 7, con = 5). Fasting insulin and C-peptide levels were significantly elevated in patients with liver cirrhosis compared with both control subjects (P <.001) and patients after OLT (P <.001). After OLT, insulin was normalized, whereas C-peptide remained elevated (P < 0.01). In the patients with liver cirrhosis, 27% had a normal glucose tolerance, 38% had an impaired glucose tolerance (IGT), and 35% were diabetic. After OLT, 34% had a normal glucose tolerance, 29% an IGT, and 37% were diabetic. Comparison of the same patients before and after OLT demonstrated that IGT or diabetes before OLT was the major risk factor for these conditions after OLT, which was independent of either immunosuppression (cyclosporine vs FK506) or low-dose prednisolone. Total glucose uptake was reduced in patients with liver cirrhosis to less than half the values in control subjects (21.2 +/- 2.8 vs 43.7 +/- 2.4 micromol/kg/minute, respectively, P <.001), whereas patients after OLT showed intermediate values (35.7 +/- 1.4 micromol/kg/minute, P < 0.05 vs con, P < 0.01 vs cir). This difference was caused by a reduction in nonoxidative glucose metabolism in patients with liver cirrhosis compared with control subjects (7.4 +/- 1.9 vs 28.7 +/- 1.8 micromol/kg/minute, respectively, P <.01) and patients after OLT (20.1 +/- 1.4 micromol/kg/minute, P < 0.05 vs con and OLT). In the PET study, skeletal muscle glucose uptake was significantly reduced in patients with liver cirrhosis compared with control subjects (3.5 +/- 0.4 vs 11.8 +/- 2.5 micromol/100g/minute, respectively, P <.05). After OLT, muscle glucose uptake improved compared with patients with liver cirrhosis (5.9 +/- 1.0 micromol/100g/minute, P <.05) but remained significantly lower than in control subjects (P <.05). In conclusion, these results demonstrate that preexisting IGT or diabetes are the major risk factors for IGT and diabetes after OLT. This finding was independent of the immunosuppressive medication. The peripheral insulin resistance in cirrhosis is characterized by a decrease in nonoxidative glucose disposal that is improved, but not normalized, after OLT.     

Effects of Gastric Bypass Surgery on the Brain: Simultaneous Assessment of Glucose Uptake,Blood Flow,Neural Activity,and Cognitive Function During Normo- and Hypoglycemia

While Roux-en-Y gastric bypass (RYGB) surgery in obese individuals typically improves glycemic control and prevents diabetes, it also frequently causes asymptomatic hypoglycemia. Previous work showed attenuated counterregulatory responses following RYGB. The underlying mechanisms as well as the clinical consequences are unclear. In this study, 11 subjects without diabetes with severe obesity were investigated pre- and post-RYGB during hyperinsulinemic normo-hypoglycemic clamps. Assessments were made of hormones, cognitive function, cerebral blood flow by arterial spin labeling, brain glucose metabolism by ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography, and activation of brain networks by functional MRI. Post- versus presurgery, we found a general increase of cerebral blood flow but a decrease of total brain FDG uptake during normoglycemia. During hypoglycemia, there was a marked increase in total brain FDG uptake, and this was similar for post- and presurgery, whereas hypothalamic FDG uptake was reduced during hypoglycemia. During hypoglycemia, attenuated responses of counterregulatory hormones and improvements in cognitive function were seen postsurgery. In early hypoglycemia, there was increased activation post- versus presurgery of neural networks in brain regions implicated in glucose regulation, such as the thalamus and hypothalamus. The results suggest adaptive responses of the brain that contribute to lowering of glycemia following RYGB, and the underlying mechanisms should be further elucidated.