Differentiated pancreatic ␤ cells are unique in their ability to secrete insulin in response to a rise in plasma glucose. We have proposed that the unique constellation of genes they express may be lost in diabetes due to the deleterious effect of chronic hyperglycemia. To test this hypothesis, Sprague-Dawley rats were submitted to a 85-95% pancreatectomy or sham pancreatectomy. One week later, the animals developed mild to severe chronic hyperglycemia that was stable for the next 3 weeks, without significant alteration of plasma nonesterified fatty acid levels. Expression of many genes important for glucose-induced insulin release decreased progressively with increasing hyperglycemia, in parallel with a reduction of several islet transcription factors involved in ␤ cell development and differentiation. In contrast, genes barely expressed in sham islets (lactate dehydrogenase A and hexokinase I) were markedly increased, in parallel with an increase in the transcription factor c-Myc, a potent stimulator of cell growth. These abnormalities were accompanied by ␤ cell hypertrophy. Changes in gene expression were fully developed 2 weeks after pancreatectomy. Correction of blood glucose by phlorizin for the next 2 weeks normalized islet gene expression and ␤ cell volume without affecting plasma nonesterified fatty acid levels, strongly suggesting that hyperglycemia triggers these abnormalities. In conclusion, chronic hyperglycemia leads to ␤ cell hypertrophy and loss of ␤ cell differentiation that is correlated with changes in c-Myc and other key transcription factors. A similar change in ␤ cell differentiation could contribute to the profound derangement of insulin secretion in human diabetes.Pancreatic ␤ cells are highly specialized cells that secrete insulin in response to a variety of stimuli, the most important being glucose (1, 2). Their correct function is dependent on the expression of a unique set of genes that allow ␤ cells to respond to even small increases in plasma glucose levels by releasing appropriate amounts of insulin into the circulation (3). Type 2 diabetes is characterized by the combination of insulin resistance and profound alteration in glucose-stimulated insulin secretion (4). The latter can be ascribed, at least in part, to the deleterious effect of even mild chronic hyperglycemia and elevated plasma nonesterified fatty acids (NEFA) 1 on pancreatic ␤ cell function, a process often referred to as "gluco-lipotoxicity" (5, 6). In islets isolated from animal models of diabetes, several defects have been identified at the level of gene expression and/or enzymatic activity, but none by itself can entirely account for the ␤ cell defect characteristic of type 2 diabetes (5,7,8).Recently, the study of the transcriptional regulation of the insulin gene has led to the identification of several ␤ cell/islet transcription factors that are important for the development of the endocrine pancreas, the tissue-specific expression of key ␤ cell genes and maintenance of ␤ cell differentiation (9, 10). In islets ...

Most studies involving spontaneous fluctuations in the BOLD signal extract connectivity patterns that show relationships between brain areas that are maintained over the length of the scanning session. In this study, however, we examine the spatiotemporal dynamics of the BOLD fluctuations to identify common patterns of propagation within a scan. A novel pattern finding algorithm was developed for detecting repeated spatiotemporal patterns in BOLD fMRI data. The algorithm was applied to high temporal resolution T2*-weighted multislice images obtained from rats and humans in the absence of any task or stimulation. In rats, the primary pattern consisted of waves of high signal intensity, propagating in a lateral to medial direction across the cortex, replicating our previous findings (Majeed et al., 2009a). These waves were observed primarily in sensorimotor cortex, but also extended to visual and parietal association areas. A secondary pattern, confined to subcortical regions consisted of an initial increase and subsequent decrease in signal intensity in the caudate-putamen. In humans, the most common spatiotemporal pattern consisted of an alteration between activation of areas comprising the "default-mode" (e.g., posterior cingulate and anterior medial prefrontal cortices) and the "task-positive" (e.g., superior parietal and premotor cortices) networks. Signal propagation from focal starting points was also observed. The pattern finding algorithm was shown to be reasonably insensitive to the variation in user-defined parameters, and the results were consistent within and between subjects. This novel approach for probing the spontaneous network activity of the brain has implications for the interpretation of conventional functional connectivity studies, and may increase the amount of information that can be obtained from neuroimaging data.

Studies have suggested that the default mode network is active during mind wandering, which is often experienced intermittently during sustained attention tasks. Conversely, an anticorrelated task-positive network is thought to subserve various forms of attentional processing. Understanding how these two systems work together is central for understanding many forms of optimal and sub-optimal task performance. Here we present a basic model of naturalistic cognitive fluctuations between mind wandering and attentional states derived from the practice of focused attention meditation. This model proposes four intervals in a cognitive cycle: mind wandering, awareness of mind wandering, shifting of attention, and sustained attention. People who train in this style of meditation cultivate their abilities to monitor cognitive processes related to attention and distraction, making them well suited to report on these mental events. Fourteen meditation practitioners performed breath-focused meditation while undergoing fMRI scanning. When participants realized their mind had wandered, they pressed a button and returned their focus to the breath. The four intervals above were then constructed around these button presses. We hypothesized that periods of mind wandering would be associated with default mode activity, whereas cognitive processes engaged during awareness of mind wandering, shifting of attention and sustained attention would engage attentional subnetworks. Analyses revealed activity in brain regions associated with the default mode during mind wandering, and in salience network regions during awareness of mind wandering. Elements of the executive network were active during shifting and sustained attention. Furthermore, activations during these cognitive phases were modulated by lifetime meditation experience. These findings support and extend theories about cognitive correlates of distributed brain networks.

This study sought to examine the effect of meditation experience on brain networks underlying cognitive actions employed during contemplative practice. In a previous study, we proposed a basic model of naturalistic cognitive fluctuations that occur during the practice of focused attention meditation. This model specifies four intervals in a cognitive cycle: mind wandering (MW), awareness of MW, shifting of attention, and sustained attention. Using subjective input from experienced practitioners during meditation, we identified activity in salience network regions during awareness of MW and executive network regions during shifting and sustained attention. Brain regions associated with the default mode were active during MW. In the present study, we reasoned that repeated activation of attentional brain networks over years of practice may induce lasting functional connectivity changes within relevant circuits. To investigate this possibility, we created seeds representing the networks that were active during the four phases of the earlier study, and examined functional connectivity during the resting state in the same participants. Connectivity maps were then contrasted between participants with high vs. low meditation experience. Participants with more meditation experience exhibited increased connectivity within attentional networks, as well as between attentional regions and medial frontal regions. These neural relationships may be involved in the development of cognitive skills, such as maintaining attention and disengaging from distraction, that are often reported with meditation practice. Furthermore, because altered connectivity of brain regions in experienced meditators was observed in a non-meditative (resting) state, this may represent a transference of cognitive abilities “off the cushion” into daily life.

Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease resulting from apoptotic destruction of β cells in the islets of Langerhans. Low expression of antioxidants and a predilection to produce nitric oxide (NO) have been shown to underscore β cell apoptosis. With this perspective in mind, we questioned whether β cells could mount an induced protective response to inflammation. Here we show that human and rat islets can be induced to rapidly express the antiapoptotic gene A20 after interleukin (IL)-1β activation. Overexpression of A20 by means of adenovirus-mediated gene transfer protects islets from IL-1β and interferon γ–induced apoptosis. The cytoprotective effect of A20 against apoptosis correlates with and is dependent on the abrogation of cytokine-induced NO production. The inhibitory effect of A20 on cytokine-stimulated NO production is due to transcriptional blockade of inducible NO synthase (iNOS) induction; A20 inhibits the activation of the transcription factor nuclear factor κB at a level upstream of IκBα degradation. These data demonstrate a dual antiapoptotic and antiinflammatory function for A20 in β cells. This qualifies A20 as part of the physiological cytoprotective response of islets. We propose that A20 may have therapeutic potential as a gene therapy candidate to achieve successful islet transplantation and the cure of IDDM.

Hypertrophy is one mechanism of pancreatic ␤-cell growth and is seen as an important compensatory response to insulin resistance. We hypothesized that the induction of protective genes contributes to the survival of enlarged (hypertrophied) ␤-cells. Here, we evaluated changes in stress gene expression that accompany ␤-cell hypertrophy in islets from hyperglycemic rats 4 weeks after partial pancreatectomy (Px). A variety of protective genes were upregulated, with markedly increased expression of the antioxidant genes heme oxygenase-1 and glutathione peroxidase and the antiapoptotic gene A20. Cu/Zn-superoxide dismutase (SOD) and Mn-SOD were modestly induced, and Bcl-2 was modestly reduced; however, several other stress genes (catalase, heat shock protein 70, and p53) were unaltered. The increases in mRNA levels corresponded to the degree of hyperglycemia and were reversed in Px rats by 2-week treatment with phlorizin (treatment that normalized hyperglycemia), strongly suggesting the specificity of hyperglycemia in eliciting the response. Hyperglycemia in Px rats also led to activation of nuclear factor-B in islets. The profound change in ␤-cell phenotype of hyperglycemic Px rats resulted in a reduced sensitivity to the ␤-cell toxin streptozotocin. Sensitivity to the toxin was restored, along with the ␤-cell phenotype, in islets from phlorizin-treated Px rats. Furthermore, ␤-cells of Px rats were not vulnerable to apoptosis when further challenged in vivo with dexamethasone, which increases insulin resistance. In conclusion, ␤-cell adaptation to chronic hyperglycemia and, hence, increased insulin demand is accompanied by the induction of protective stress genes that may contribute to the survival of hypertrophied ␤-cells. Diabetes 51:413-423, 2002 E xpansion of islet ␤-cell mass represents an important compensatory mechanism to maintain normoglycemia in the face of insulin resistance and obesity (1-5). An increase in ␤-cell mass accompanies insulin resistance induced in rats by glucocorticoid treatment (6) and in mice by mutation of the insulin receptor or insulin receptor substrate-1 (1). In humans, there is evidence that ␤-cell mass is increased in obese subjects compared with lean control subjects (7). In rodents, there is substantial evidence that increases in ␤-cell size (hypertrophy), replication, and neogenesis occur in situations of an increased insulin demand. For example, partial pancreatectomy (Px) in rats induces active neogenesis and ␤-cell replication within the first 7 days (8,9), and by 4 weeks, moderate chronic hyperglycemia produces ␤-cell hypertrophy (3,10). Hypertrophy has also been found in rats after chronic glucose infusion (11), in prediabetic ZDF-fa/fa rats with impaired glucose tolerance (2), and in pregnancy (12).During the progression to type 2 diabetes, the capacity for compensatory ␤-cell expansion may be overwhelmed, leading to decompensation (2,4,5,13-15). Reduction in ␤-cell mass secondary to an increased rate of apoptosis has been implicated (2,13,15). Recent experiments show that ...

Although type 2 diabetes mellitus is associated with insulin resistance, many individuals compensate by increasing insulin secretion. Putative mechanisms underlying this compensation were assessed in the present study by use of 4-day glucose (GLC; 35% Glc, 2 ml/h) and lipid (LIH; 10% Intralipid + 20 U/ml heparin; 2 ml/h) infusions to rats. Within 2 days of beginning the infusion of either lipid or glucose, plasma glucose profiles were normalized (relative to saline-infused control rats; SAL; 0.45% 2 ml/h). During glucose infusion, plasma glucose was maintained in the normal range by an approximately twofold increase in plasma insulin and an approximately 80% increase in beta-cell mass. During LIH infusion, glucose profiles were also maintained in the normal range. Plasma insulin responses during feeding were doubled, and beta-cell mass increased 54%. For both groups, the increase in beta-cell mass was associated with increased beta-cell proliferation (98% increase during GLC and 125% increase during LIH). At the end of the 4-day infusions, no significant changes were observed in islet-specific gene transcription (i.e., the expression of islet hormone genes, glucose metabolism genes, and insulin transcription factors were unaffected). Two days after termination of the infusions, the glucose-stimulated plasma insulin response was increased approximately 67% in glucose-infused animals. No sustained effect on insulin secretory capacity was observed in the LIH animals. The increase in plasma insulin response after glucose infusion was achieved in the absence of any change in insulin clearance. We conclude that, in rats, an increase in insulin demand after an increase in glucose appearance or free fatty acid leads to an increase in beta-cell mass, mediated in part by an increase in beta-cell proliferation, and that these compensatory changes lead to increased insulin secretion, normal plasma glucose levels, and the maintenance of normal islet gene expression.

Prepulse inhibition (PPI) is an acoustic startle paradigm that has been used as an operational measure of sensorimotor gating. Many patients with schizophrenia have impaired PPI, and several lines of evidence suggest that PPI may represent a heritable endophenotype in this disease. We examined startle magnitude and latencies in 40 schizophrenia patients, 58 first-degree relatives of these patients and 100 healthy controls. After removing low-startlers, we investigated PPI and startle habituation in 34 schizophrenia patients, 43 relatives and 86 control subjects. Heritability analyses were conducted using a variance-component approach. We found significant heritability of 45% for PPI at the 60-ms interval and 67% for startle magnitude. Onset latency heritability estimates ranged between 39% and 90% across trial types, and those for peak latency ranged from 29% to 68%. Heritability of startle habituation trended toward significance at 31%. We did not detect differences between controls and either schizophrenia patients or their family members for PPI, startle magnitude or habituation. Startle latencies were generally longer in schizophrenia patients than controls. The heritability findings give impetus to applying genetic analyses to PPI variables, and suggest that startle latency may also be a useful measure in the study of potential endophenotypes for schizophrenia.