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, HbA1c = 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

Network-Level Structural Abnormalities of Cerebral Cortex in Type 1 Diabetes Mellitus

Type 1 diabetes mellitus (T1DM) usually begins in childhood and adolescence and causes lifelong damage to several major organs including the brain. Despite increasing evidence of T1DM-induced structural deficits in cortical regions implicated in higher cognitive and emotional functions, little is known whether and how the structural connectivity between these regions is altered in the T1DM brain. Using inter-regional covariance of cortical thickness measurements from high-resolution T1-weighted magnetic resonance data, we examined the topological organizations of cortical structural networks in 81 T1DM patients and 38 healthy subjects. We found a relative absence of hierarchically high-level hubs in the prefrontal lobe of T1DM patients, which suggests ineffective top-down control of the prefrontal cortex in T1DM. Furthermore, inter-network connections between the strategic/executive control system and systems subserving other cortical functions including language and mnemonic/emotional processing were also less integrated in T1DM patients than in healthy individuals. The current results provide structural evidence for T1DM-related dysfunctional cortical organization, which specifically underlie the top-down cognitive control of language, memory, and emotion. © 2013 Lyoo et al

High-throughput mediation analysis of human proteome and metabolome identifies mediators of post-bariatric surgical diabetes control

To improve the power of mediation in high-throughput studies, here we introduce High-throughput mediation analysis (Hitman), which accounts for direction of mediation and applies empirical Bayesian linear modeling. We apply Hitman in a retrospective, exploratory analysis of the SLIMM-T2D clinical trial in which participants with type 2 diabetes were randomized to Roux-en-Y gastric bypass (RYGB) or nonsurgical diabetes/weight management, and fasting plasma proteome and metabolome were assayed up to 3 years. RYGB caused greater improvement in HbA1c, which was mediated by growth hormone receptor (GHR). GHR’s mediation is more significant than clinical mediators, including BMI. GHR decreases at 3 months postoperatively alongside increased insulin-like growth factor binding proteins IGFBP1/BP2; plasma GH increased at 1 year. Experimental validation indicates (1) hepatic GHR expression decreases in post-bariatric rats; (2) GHR knockdown in primary hepatocytes decreases gluconeogenic gene expression and glucose production. Thus, RYGB may induce resistance to diabetogenic effects of GH signaling

No Reliable Association between Runs of Homozygosity and Schizophrenia in a Well-Powered Replication Study

It is well known that inbreeding increases the risk of recessive monogenic diseases, but it is less certain whether it contributes to the etiology of complex diseases such as schizophrenia. One way to estimate the effects of inbreeding is to examine the association between disease diagnosis and genome-wide autozygosity estimated using runs of homozygosity (ROH) in genome-wide single nucleotide polymorphism arrays. Using data for schizophrenia from the Psychiatric Genomics Consortium (n = 21,868), Keller et al. (2012) estimated that the odds of developing schizophrenia increased by approximately 17% for every additional percent of the genome that is autozygous (β = 16.1, CI(β) = [6.93, 25.7], Z = 3.44, p = 0.0006). Here we describe replication results from 22 independent schizophrenia case-control datasets from the Psychiatric Genomics Consortium (n = 39,830). Using the same ROH calling thresholds and procedures as Keller et al. (2012), we were unable to replicate the significant association between ROH burden and schizophrenia in the independent PGC phase II data, although the effect was in the predicted direction, and the combined (original + replication) dataset yielded an attenuated but significant relationship between Froh and schizophrenia (β = 4.86,CI(β) = [0.90,8.83],Z = 2.40,p = 0.02). Since Keller et al. (2012), several studies reported inconsistent association of ROH burden with complex traits, particularly in case-control data. These conflicting results might suggest that the effects of autozygosity are confounded by various factors, such as socioeconomic status, education, urbanicity, and religiosity, which may be associated with both real inbreeding and the outcome measures of interest

Phase Behavior of Aqueous Na-K-Mg-Ca-CI-NO3 Mixtures: Isopiestic Measurements and Thermodynamic Modeling

A comprehensive model has been established for calculating thermodynamic properties of multicomponent aqueous systems containing the Na{sup +}, K{sup +}, Mg{sup 2+}, Ca{sup 2+}, Cl{sup -}, and NO{sub 3}{sup -} ions. The thermodynamic framework is based on a previously developed model for mixed-solvent electrolyte solutions. The framework has been designed to reproduce the properties of salt solutions at temperatures ranging from the freezing point to 300 C and concentrations ranging from infinite dilution to the fused salt limit. The model has been parameterized using a combination of an extensive literature database and new isopiestic measurements for thirteen salt mixtures at 140 C. The measurements have been performed using Oak Ridge National Laboratory's (ORNL) previously designed gravimetric isopiestic apparatus, which makes it possible to detect solid phase precipitation. Water activities are reported for mixtures with a fixed ratio of salts as a function of the total apparent salt mole fraction. The isopiestic measurements reported here simultaneously reflect two fundamental properties of the system, i.e., the activity of water as a function of solution concentration and the occurrence of solid-liquid transitions. The thermodynamic model accurately reproduces the new isopiestic data as well as literature data for binary, ternary and higher-order subsystems. Because of its high accuracy in calculating vapor-liquid and solid-liquid equilibria, the model is suitable for studying deliquescence behavior of multicomponent salt systems

A Single Institution’s Overweight Pediatric Population and Their Associated Comorbid Conditions

Background:. Obesity studies are often performed on population data. We sought to examine the incidence of obesity and its associated comorbidities in a single freestanding children's hospital. Methods:. We performed a retrospective analysis of all visits to Boston Children's Hospital from 2000 to 2012. This was conducted to determine the incidence of obesity, morbid obesity, and associated comorbidities. Each comorbidity was modeled independently. Incidence rate ratios were calculated, as well as odds ratios. Results:. A retrospective review of 3,185,658 person-years in nonobese, 26,404 person-years in obese, and 25,819 person-years in the morbidly obese was conducted. Annual rates of all major comorbidities were increased in all patients, as well as in our obese and morbidly obese counterparts. Incidence rate ratios (IRR) and odds ratios (OR) were also significantly increased across all conditions for both our obese and morbidly obese patients. Conclusions:. These data illustrate the substantial increases in obesity and associated comorbid conditions. Study limitations include (1) single institution data, (2) retrospective design, and (3) administrative undercoding. Future treatment options need to address these threats to longevity and quality of life

Effects of Gastric Bypass and Gastric Banding on Bone Remodeling in Obese Patients with Type 2 Diabetes

CONTEXT: Roux-en-Y gastric bypass (RYGB) leads to high-turnover bone loss, but little is known about skeletal effects of laparoscopic adjustable gastric banding (LAGB) or mechanisms underlying bone loss after bariatric surgery. OBJECTIVE: To evaluate effects of RYGB and LAGB on fasting and postprandial indices of bone remodeling. DESIGN AND SETTING: Ancillary investigation of a prospective study at 2 academic institutions. PARTICIPANTS: Obese adults aged 21–65 years with type 2 diabetes who underwent RYGB (n = 11) or LAGB (n = 8). OUTCOMES: Serum C-terminal telopeptide (CTX), procollagen type 1 N-terminal propeptide (P1NP), and PTH were measured during a mixed meal tolerance test at baseline, 10 days and 1 year after surgery. Changes in 25-hydroxyvitamin D, polypeptide YY (PYY), glucagon-like peptide-1, glucose-dependent insulinotropic peptide, and insulin were also assessed. RESULTS: Fasting CTX increased 10 days after RYGB but not LAGB (+69 ± 23% vs +12±12%, P < .001), despite comparable weight loss at that time. By 1 year, fasting CTX and P1NP increased more after RYGB than LAGB (CTX +221 ± 60% vs +15 ± 6%, P<0.001; P1NP +93 ± 25% vs −9 ± 10%, P < .001) and weight loss was greater with RYGB. Changes in CTX were independent of PTH and 25-hydroxyvitamin D but were associated with increases in fasting PYY. Postprandial suppression of CTX was more pronounced after RYGB than LAGB at 10 days and 1 year postoperatively. CONCLUSIONS: RYGB is accompanied by early increases in fasting indices of bone remodeling, independent of weight loss or changes in PTH or 25-hydroxyvitamin D. LAGB did not affect bone markers. PYY and other enterohormonal signals may play a role in RYGB-specific skeletal changes