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Publications (174)
Regulation of blood glucose levels depends on the property of beta cells to couple glucose sensing with insulin secretion. This is accomplished by the concentration-dependent flux of glucose through glycolysis and oxidative phosphorylation, generating ATP. The resulting rise in cytosolic ATP/ADP inhibits KATP channels, inducing membrane depolarizat...
Primary defects in folding of mutant proinsulin can cause dominant‐negative proinsulin accumulation in the endoplasmic reticulum (ER), impaired anterograde proinsulin trafficking, perturbed ER homeostasis, diminished insulin production, and β‐cell dysfunction. Conversely, if primary impairment of ER‐to‐Golgi trafficking (which also perturbs ER home...
Pancreatic beta cells secrete insulin in response to plasma glucose. The ATP‐sensitive potassium channel (KATP) links glucose metabolism to islet electrical activity in these cells by responding to increased cytosolic [ATP]/[ADP]. It was recently proposed that pyruvate kinase (PK) in close proximity to beta cell KATP locally produces the ATP that i...
The importance of sexual dimorphism has been highlighted in recent years since the National Institutes of Health's mandate on considering sex as a biological variable. Although recent studies have taken strides to study both sexes side by side, investigations into the normal physiological differences between males and females are limited. In this s...
Pancreatic beta cells maintain glucose homeostasis by secreting pulses of insulin in response to a rise in plasma glucose. Pulsatile insulin secretion occurs as a result of glucose-induced oscillations in beta-cell cytosolic Ca2+. The endoplasmic reticulum (ER) helps regulate beta-cell cytosolic Ca2+, and ER stress can lead to ER Ca2+ reduction, be...
The standard model for Ca2+ oscillations in insulin-secreting pancreatic beta cells centers on Ca2+ entry through voltage-activated Ca2+ channels. These work in combination with ATP-dependent K+ channels, which are the bridge between the metabolic state of the cells and plasma membrane potential. This partnership underlies the ability of the beta c...
The free calcium (Ca2+) levels in pancreatic beta cell organelles have been the subject of many recent investigations. Under pathophysiological conditions, disturbances in these pools have been linked to altered intracellular communication and cellular dysfunction. To facilitate studies of subcellular Ca2+ signaling in beta cells and, particularly,...
Pancreatic beta cells maintain glucose homeostasis by secreting pulses of insulin in response to a rise in glucose. Pulsatile secretion occurs due to glucose-induced oscillations in beta-cell cytosolic Ca ²⁺ . The endoplasmic reticulum (ER) helps regulate beta-cell cytosolic Ca ²⁺ , and ER stress can lead to ER Ca ²⁺ depletion, beta-cell dysfunctio...
Mitochondrial dysfunction is a hallmark of metabolic diseases, including diabetes, yet the downstream consequences of mitochondrial damage in metabolic tissues are often unclear. Here, we report that mitochondrial dysfunction engages a retrograde signaling program that impairs cellular identity and maturity across many metabolic tissues. Impairment...
We recently reported that normal pancreatic islets or beta cell lines contain a subset of proinsulin molecules that have not achieved the three intramolecular disulfide bonds required for native insulin structure. Indeed, we found that non-native proinsulin monomers can form intermolecular disulfide-linked complexes, which are detectable by immunob...
In fasted and fed states, blood insulin levels are oscillatory. While this phenomenon is well studied at high glucose levels, comparatively little is known about its origin under basal conditions. We propose a possible mechanism for basal insulin oscillations based on oscillations in glycolysis, demonstrated using an established mathematical model....
ATP-sensitive K⁺ (K(ATP)) channels were first reported in the beta-cells of pancreatic islets in 1984, and it was soon established that they are the primary means by which the blood glucose level is transduced to cellular electrical activity and consequently insulin secretion. However, the role that the K(ATP) channels play in driving the bursting...
Pulsatile insulin secretion by pancreatic beta cells is necessary for tight glucose control in the body. Glycolytic oscillations have been proposed as the mechanism for generating the electrical oscillations underlying pulsatile insulin secretion. The glycolytic enzyme 6-phosphofructokinase-1 (PFK) synthesizes fructose-1,6-bisphosphate (FBP) from f...
Insulin is secreted in a pulsatile pattern, with important physiological ramifications. In pancreatic β-cells, which are the cells that synthesize insulin, insulin exocytosis is elicited by pulses of elevated intracellular Ca²⁺ initiated by bursts of electrical activity. In parallel with these electrical and Ca²⁺ oscillations are oscillations in me...
Beta cells of the pancreatic islet express many different types of ion channels. These channels reside in the β-cell plasma membrane as well as subcellular organelles and their coordinated activity and sensitivity to metabolism regulate glucose-dependent insulin secretion. Here, we review the molecular nature, expression patterns, and functional ro...
Type 2 diabetes (T2D) is a metabolic disorder characterized by hyperglycemia, hyperinsulinemia, and insulin resistance (IR). During the early phase of T2D, insulin synthesis and secretion by pancreatic b cells is enhanced, which can lead to proinsulin misfolding that aggravates endoplasmic reticulum (ER) protein homeostasis in cells. Moreover, in...
Both type 1 and type 2 diabetes mellitus are advancing at exponential rates, placing significant burdens on health care networks worldwide. Although traditional pharmacologic therapies such as insulin and oral antidiabetic stalwarts like metformin and the sulfonylureas continue to be used, newer drugs are now on the market targeting novel blood glu...
Pancreatic beta cells maintain glucose homeostasis by secreting insulin following a rise in plasma glucose. Insulin secretion is pulsatile, which is brought about because of oscillations in the concentrations of beta-cell cytosolic Ca2+. The endoplasmic reticulum (ER) helps to regulate the cytosolic Ca2+ level, thereby playing a role in Ca2+-induce...
The endoplasmic reticulum (ER) is an organelle that mediates the proper folding and assembly of proteins destined for the cell surface, the extracellular space and subcellular compartments such as the lysosomes. The ER contains a wide range of molecular chaperones to handle the folding requirements of a diverse set of proteins that traffic through...
Secretory protein misfolding has been linked to ER stress and cell death. We expressed a TGrdw transgene encoding TG-G(2298)R, a misfolded mutant thyroglobulin reported to be linked to thyroid cell death. When the TGrdw transgene was expressed at low-level in thyrocytes of TGcog/cog mice that experience severe ER stress, we observed increased thyro...
Pancreatic β-cell dysfunction is central to the development and progression of type 2 diabetes. Dysregulation of miRNAs has been associated with pancreatic islet dysfunction in type 2 diabetes. Previous study has shown that miR-483 is expressed relatively higher in β-cells than in α-cells. To explore the physiological function of miR-483, we genera...
Inflammatory damage contributes to β cell failure in type 1 and 2 diabetes (T1D and T2D, respectively). Mitochondria are damaged by inflammatory signaling in β cells, resulting in impaired bioenergetics and initiation of proapoptotic machinery. Hence, the identification of protective responses to inflammation could lead to new therapeutic targets....
Inflammatory damage contributes to β-cell failure in type 1 and 2 diabetes (T1D and T2D). Mitochondria are damaged by inflammatory signaling in β-cells, resulting in impaired bioenergetics and initiation of pro-apoptotic machinery. Hence, the identification of protective responses to inflammation could lead to new therapeutic targets. Here we repor...
Type 2 diabetes mellitus (T2DM) is characterized by impaired glucose-stimulated insulin secretion and increased peripheral insulin resistance. Unremitting ER stress can lead to b-cell apoptosis and has been linked to type 2 diabetes. Although many studies have attempted to link ER stress and T2DM, the specific effects of ER stress on b-cell functio...
Pancreatic islets produce pulses of insulin and other hormones that maintain normal glucose homeostasis. These micro-organs possess exquisite glucose-sensing capabilities, allowing for precise changes in pulsatile insulin secretion in response to small changes in glucose. When communication among these cells is disrupted, precision glucose sensing...
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
The islet in type 2 diabetes (T2D) is characterized by amyloid deposits derived from islet amyloid polypeptide (IAPP), a protein co-expressed with insulin by β-cells. In common with amyloidogenic proteins implicated in neurodegeneration, human IAPP (hIAPP) forms membrane permeant toxic oligomers implicated in misfolded protein stress. Here, we esta...
Pancreatic β-cells are exquisitely sensitive to developmental nutrient stressors, and alterations in nutrient sensing pathways may underlie changes observed in these models. Here we developed a mouse model of in utero exposure to the anti-diabetic agent metformin. We have previously shown that this exposure increases offspring pancreatic β-cell mas...
Insulin secretion from pancreatic islet β-cells occurs in a pulsatile fashion, with a typical period of ∼5 min. The basis of this pulsatility in mouse islets has been investigated for more than four decades, and the various theories have been described as either qualitative or mathematical models. In many cases the models differ in their mechanisms...
Cell replication is a fundamental attribute of growth and repair in multicellular organisms. Pancreatic beta-cells in adults rarely enter cell cycle, hindering the capacity for regeneration in diabetes. Efforts to drive beta-cells into cell cycle have so far largely focused on regulatory molecules such as cyclins and cyclin-dependent kinases (CDKs)...
Plasma insulin oscillations are known to have physiological importance in the regulation of blood glucose. In insulin-secreting β-cells of pancreatic islets, K(ATP) channels play a key role in regulating glucose-dependent insulin secretion. In addition, they convey oscillations in cellular metabolism to the membrane by sensing adenine nucleotides,...
Data for Fig 3B, calcium oscillations in a knockout islet.
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Data for Fig 7B, application of 8-Br-cAMP to 9 knockout islets.
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Data for Fig 11B, application of Tg to 10 knockout islets.
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Model equations and parameters.
Equations and parameter values for the model.
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Data for Fig 3A, calcium oscillations in a wild-type islet.
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Data for Fig 3C, I-V curves for wild-type and knockout islets.
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Data for Fig 7A, application of 8-Br-cAMP to 11 wild-type islets.
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Data for Fig 11D, application of Tg to 14 wild-type islets.
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Regulation of glucose homeostasis by insulin depends on β-cell growth and function. Nutrients and growth factors stimuli converge on the conserved protein kinase mechanistic target of rapamycin (mTOR), existing in two complexes mTORC1 and mTORC2. To understand the functional relevance of mTOR enzymatic activity in β-cell development and in glucose...
The failure of pancreatic islet β-cells is a major contributor to the etiology of Type 2 diabetes. β-cell dysfunction and declining β-cell mass are two mechanisms that contribute to this failure, although it is unclear if they are molecularly linked. Here, we show that the cell cycle regulator, cyclin-dependent kinase 2 (Cdk2), couples primary β-ce...
Inflammatory breast cancer (IBC) is an extremely lethal cancer that rapidly metastasizes. While the molecular attributes of
IBC have been described, little is known about the underlying metabolic features of the disease. Using a variety of metabolic
assays including 13C tracer experiments, we found that SUM149 cells, the primary in vitro model of I...
Pancreatic islets respond to elevated blood glucose by secreting pulses of insulin that parallel oscillations in β-cell metabolism, intracellular Ca2+ concentration, and bursting electrical activity. The mechanisms that maintain an oscillatory response are not fully understood, yet several models have been proposed. Only some can account for experi...
Metabolism in islet β-cells displays oscillations that can trigger pulses of electrical activity and insulin secretion. There has been a decades-long debate among islet biologists about whether metabolic oscillations are intrinsic or occur in response to oscillations in intracellular Ca(2+) that result from bursting electrical activity. In this art...
The closing of beta cell K(ATP) channels acutely triggers glucose-induced insulin secretion. However, the trafficking of K(ATP) channels to the beta cell plasma membrane has recently been shown to regulate beta cell secretory function over a longer time course, and changes in the number of K(ATP) channels can help set islet glucose sensitivity. To...
Type 2 diabetes (T2D) is generally thought to result from the combination of two metabolic defects, insulin resistance, which increases the level of insulin required to maintain glucose within the normal range, and failure of insulin-secreting pancreatic beta cells to compensate for the increased demand. We build on a mathematical model pioneered b...
Mouse islets exhibit glucose-dependent oscillations in electrical activity, intracellular Ca(2+) and insulin secretion. We developed a mathematical model in which a left shift in glucose threshold helps compensate for insulin resistance (companion paper: Ha, Satin, and Sherman). To test this experimentally we exposed isolated mouse islets to varyin...
Nutrient levels dictate the activity of O-linked N-acetylglucosamine transferase (OGT) to regulate O-GlcNAcylation, a post-translational modification mechanism to “fine-tune” intracellular signaling and metabolic status. However, the requirement of O-GlcNAcylation for maintaining glucose homeostasis by regulating pancreatic β cell mass and function...
miR-153 is an intronic miRNA embedded in the genes that encode IA-2 (also known as PTPRN) and IA-2β (also known as PTPRN2). Islet antigen (IA)-2 and IA-2β are major autoantigens in type 1 diabetes and are important transmembrane proteins in dense core and synaptic vesicles. miR-153 and its host genes are co-regulated in pancreas and brain. The pres...
Type 2 diabetes (T2DM) results when increases in beta cell function and/or mass cannot compensate for rising insulin resistance. Numerous studies have documented the longitudinal changes in metabolism that occur during the development of glucose intolerance and lead to T2DM. However, the role of changes in insulin secretion, both amount and tempora...
Pancreatic islets of SUR1-/- mice exhibit electrical oscillations even though they lack KATP channels. However, while we confirmed that electrical oscillations persisted in freshly isolated SUR1-/- islets, after overnight culture in media containing 11.1 mM glucose, SUR1-/- islets exhibited continuous spiking in place of oscillations, as has been o...
Oscillations are an integral part of insulin secretion and are due ultimately to oscillations in the electrical activity of pancreatic β-cells, called bursting. We discuss the underlying mechanisms for bursting oscillations in mouse islets and the parallel oscillations in intracellular calcium and metabolism. We present a unified biophysical model,...
Insulin is released from the islets of Langerhans in discrete pulses that are linked to synchronized oscillations of intracellular free calcium ([Ca(2+)]i). Associated with each synchronized oscillation is a propagating calcium wave mediated by Connexin36 (Cx36) gap junctions. A computational islet model predicted that waves emerge due to heterogen...
Hypoglycemia initiates the counter-regulatory response (CRR), in which the sympathetic nervous system, glucagon and glucocorticoids restore glucose to appropriate concentrations. During starvation, low leptin levels restrain energy utilization, enhancing long-term survival. To ensure short-term survival during hypoglycemia in fasted animals, the CR...
While the Pancreatic duodenal homeobox 1 (Pdx-1) transcription factor is known to play an indispensable role in β cell development and secretory function, recent data also implicate Pdx-1 in the maintenance of endoplasmic reticulum (ER) health. The sarco endoplasmic reticulum Ca(2+) ATPase 2b (SERCA2b) pump maintains a steep Ca(2+) gradient between...
Administration of maternal diet low in protein increases the susceptibility of offspring to type 2 diabetes by inducing long-term alterations in β cell mass and function. Nutrients and growth factor signaling converge through mTOR, suggesting that this pathway participates in β cell programming during fetal development. Here, we revealed that newbo...
The adipocyte-derived hormone leptin modulates neural systems appropriately for the status of body energy stores. Leptin inhibits lateral hypothalamic area (LHA) orexin (OX; also known as hypocretin)-producing neurons, which control feeding, activity, and energy expenditure, among other parameters. Our previous results suggest that GABAergic LHA le...
We investigated commonly used methods (Autocorrelation, Enright, and Discrete Fourier Transform) to estimate the periodicity of oscillatory data and determine which method most accurately estimated periods while being least vulnerable to the presence of noise. Both simulated and experimental data were used in the analysis performed. We determined t...
Pancreatic islets exhibit bursting oscillations in response to elevated blood glucose. These oscillations are accompanied by oscillations in the free cytosolic Ca 2+ concentration (Ca c ), which drives pulses of insulin secretion. Both islet Ca 2+ and metabolism oscillate, but there is some debate about their interrelationship. Recent experimental...
Rhythms govern many endocrine functions. Examples of such rhythmic systems include the insulin-secreting pancreatic beta-cell, which regulates blood glucose, and the gonadotropin-releasing hormone (GnRH) neuron, which governs reproductive function. Although serving very different functions within the body, these cell types share many important feat...
The secretion of insulin from pancreatic islet beta cells is pulsatile (∼5 min period) and reflects upstream oscillations in metabolism and Ca2+. Of the oscillating pathways in the beta cell, glycolytic oscillations are the least well studied. We recently developed a FRET biosensor for pyruvate kinase M2 activity (PKAR, Pyruvate Kinase Activity Rep...
Pulses of insulin released from pancreatic β-cells maintain blood glucose in a narrow range, although the source of these pulses is unclear. We and others have proposed that positive feedback mediated by the glycolytic enzyme phosphofructokinase-1 (PFK1) enables β-cells to generate metabolic oscillations via autocatalytic activation by its product...
We used the patch clamp technique in situ to test the hypothesis that slow oscillations in metabolism mediate slow electrical oscillations in mouse pancreatic islets by causing oscillations in KATP channel activity. Total conductance was measured over the course of slow bursting oscillations in surface β-cells of islets exposed to 11.1 mM glucose b...
Alterations in the function and expression of NMDA receptors are observed after in vivo and in vitro traumatic brain injury. We recently reported that mechanical stretch injury in cortical neurons transiently increases the contribution of NMDA receptors to network activity and results in an increase in CP-AMPA receptor-mediated transmission 4 hours...
AIMS AND HYPOTHESIS: Glucose-stimulated insulin secretion from beta-cells is a tightly regulated process that requires calcium flux to trigger exocytosis of insulin-containing vesicles. Regulation of calcium handling in beta-cells remains incompletely understood. Gem, a member of the RGK (Rad/Gem/Kir) family regulates calcium channel handling in ot...