Maintenance Of Blood Glucose Homeostasis Research Articles

Optogenetics in pancreatic islets: Actuators and effects.

The Islets of Langerhans reside within the endocrine pancreas as highly vascularised micro-organs that are responsible for the secretion of key hormones, such as insulin and glucagon. Islet function relies on a range of dynamic molecular processes that include calcium (Ca2+) waves, hormone pulses, and complex interactions between islet cell types. Dysfunction of these processes results in poor maintenance of blood glucose homeostasis and is a hallmark of diabetes. Very recently, the development of optogenetic methods that rely on light-sensitive molecular actuators has allowed perturbing islet function with near physiological spatio-temporal acuity. These actuators harness natural photoreceptor proteins and their engineered variants to manipulate mouse and human cells that are not normally light-responsive. Until recently, optogenetics in islet biology has primarily focused on hormone production and secretion; however, studies on further aspects of islet function, including paracrine regulation between islet cell types and dynamics within intracellular signaling pathways are emerging. Here, we discuss the applicability of optogenetics to islets cells and comprehensively review seminal as well as recent work on optogenetic actuators and their effects in islet function and diabetes mellitus (DM).

An integrative profiling of metabolome and transcriptome in the plasma and skeletal muscle following an exercise intervention in diet-induced obese mice.

Exercise intervention at the early stage of type 2 diabetes mellitus (T2DM) can aid in the maintenance of blood glucose homeostasis and prevent the development of macrovascular and microvascular complications. However, the exercise-regulated pathways that prevent the development of T2DM remain largely unclear. In this study, two forms of exercise intervention, treadmill training and voluntary wheel running, were conducted for high-fat diet (HFD)-induced obese mice. We observed that both forms of exercise intervention alleviated HFD-induced insulin resistance and glucose intolerance. Skeletal muscle is recognized as the primary site for postprandial glucose uptake and for responsive alteration beyond exercise training. Metabolomic profiling of the plasma and skeletal muscle in Chow, HFD, and HFD-exercise groups revealed robust alterations in metabolic pathways by exercise intervention in both cases. Overlapping analysis identified nine metabolites, including beta-alanine, leucine, valine, and tryptophan, which were reversed by exercise treatment in both the plasma and skeletal muscle. Transcriptomic analysis of gene expression profiles in the skeletal muscle revealed several key pathways involved in the beneficial effects of exercise on metabolic homeostasis. In addition, integrative transcriptomic and metabolomic analyses uncovered strong correlations between the concentrations of bioactive metabolites and the expression levels of genes involved in energy metabolism, insulin sensitivity, and immune response in the skeletal muscle. This work established two models of exercise intervention in obese mice and provided mechanistic insights into the beneficial effects of exercise intervention on systemic energy homeostasis.

Effects of Berberine against Pancreatitis and Pancreatic Cancer

The pancreas is a glandular organ with endocrine and exocrine functions necessary for the maintenance of blood glucose homeostasis and secretion of digestive enzymes. Pancreatitis is characterized by inflammation of the pancreas leading to temporary or permanent pancreatic dysfunction. Inflammation and fibrosis caused by chronic pancreatitis exacerbate malignant transformation and significantly increase the risk of developing pancreatic cancer, the world's most aggressive cancer with a 5-year survival rate less than 10%. Berberine (BBR) is a naturally occurring plant-derived polyphenol present in a variety of herbal remedies used in traditional medicine to treat ulcers, infections, jaundice, and inflammation. The current review summarizes the existing in vitro and in vivo evidence on the effects of BBR against pancreatitis and pancreatic cancer with a focus on the signalling mechanisms underlying the effects of BBR.

The many facets of CD26/dipeptidyl peptidase 4 and its inhibitors in disorders of the CNS- a critical overview.

Dipeptidyl peptidase 4 is a serine protease that cleaves X-proline or X-alanine in the penultimate position. Natural substrates of the enzyme are glucagon-like peptide-1, glucagon inhibiting peptide, glucagon, neuropeptide Y, secretin, substance P, pituitary adenylate cyclase-activating polypeptide, endorphins, endomorphins, brain natriuretic peptide, beta-melanocyte stimulating hormone and amyloid peptides as well as some cytokines and chemokines. The enzyme is involved in the maintenance of blood glucose homeostasis and regulation of the immune system. It is expressed in many organs including the brain. DPP4 activity may be effectively depressed by DPP4 inhibitors. Apart from enzyme activity, DPP4 acts as a cell surface (co)receptor, associates with adeosine deaminase, interacts with extracellular matrix, and controls cell migration and differentiation. This review aims at revealing the impact of DPP4 and DPP4 inhibitors for several brain diseases (virus infections affecting the brain, tumours of the CNS, neurological and psychiatric disorders). Special emphasis is given to a possible involvement of DPP4 expressed in the brain.While prominent contributions of extracerebral DPP4 are evident for a majority of diseases discussed herein; a possible role of "brain" DPP4 is restricted to brain cancers and Alzheimer disease. For a number of diseases (Covid-19 infection, type 2 diabetes, Alzheimer disease, vascular dementia, Parkinson disease, Huntington disease, multiple sclerosis, stroke, and epilepsy), use of DPP4 inhibitors has been shown to have a disease-mitigating effect. However, these beneficial effects should mostly be attributed to the depression of "peripheral" DPP4, since currently used DPP4 inhibitors are not able to pass through the intact blood-brain barrier.

Acute bioenergetic insulin sensitivity of skeletal muscle cells: ATP-demand-provoked glycolysis contributes to stimulation of ATP supply

Skeletal muscle takes up glucose in an insulin-sensitive manner and is thus important for the maintenance of blood glucose homeostasis. Insulin resistance during development of type 2 diabetes is associated with decreased ATP synthesis, but the causality of this association is controversial. In this paper, we report real-time oxygen uptake and medium acidification data that we use to quantify acute insulin effects on intracellular ATP supply and ATP demand in rat and human skeletal muscle cells. We demonstrate that insulin increases overall cellular ATP supply by stimulating the rate of glycolytic ATP synthesis. Stimulation is immediate and achieved directly by increased glycolytic capacity, and indirectly by elevated ATP demand from protein synthesis. Raised glycolytic capacity does not result from augmented glucose uptake. Notably, insulin-sensitive glucose uptake is increased synergistically by nitrite. While nitrite has a similar stimulatory effect on glycolytic ATP supply as insulin, it does not amplify insulin stimulation. These data highlight the multifarious nature of acute bioenergetic insulin sensitivity of skeletal muscle cells, and are thus important for the interpretation of changes in energy metabolism that are seen in insulin-resistant muscle.

Small molecules released from islets of Langerhans determined by liquid chromatography - mass spectrometry.

Islets of Langerhans are the endocrine tissue within the pancreas that secrete hormones for maintenance of blood glucose homeostasis. A variety of small molecules including classical neurotransmitters are also released from islets. While the roles of most of these small molecules are unknown, some have been hypothesized to play a critical role in islet physiology. To better understand their role on islet function, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed to separate and quantify 39 small molecules released from islets. Benzoyl chloride derivatization of analyte molecules was used to impart retention and facilitate electrospray ionization efficiency. Separation was achieved on a 2.1 × 150 mm column packed with 2.7 μm core–shell C18 particles. Calibration curves showed excellent linearity between the concentration and analyte response, with relative standard deviations of the analyte responses below 15% and limits of detection from 0.01–40 nM. The method was applied to examine small molecules released from murine and human islets of Langerhans after static incubation and perfusion with glucose. Results showed a decrease in secretion rates with increasing glucose concentration for most of the analytes. Secretion rates were found to be higher in human islets compared to their murine counterpart. This method will be useful in understanding the roles of small molecules in biological systems.

The Eye as a Transplantation Site to Monitor Pancreatic Islet Cell Plasticity.

The endocrine cells confined in the islets of Langerhans are responsible for the maintenance of blood glucose homeostasis. In particular, beta cells produce and secrete insulin, an essential hormone regulating glucose uptake and metabolism. An insufficient amount of beta cells or defects in the molecular mechanisms leading to glucose-induced insulin secretion trigger the development of diabetes, a severe disease with epidemic spreading throughout the world. A comprehensive appreciation of the diverse adaptive procedures regulating beta cell mass and function is thus of paramount importance for the understanding of diabetes pathogenesis and for the development of effective therapeutic strategies. While significant findings were obtained by the use of islets isolated from the pancreas, in vitro studies are inherently limited since they lack the many factors influencing pancreatic islet cell function in vivo and do not allow for longitudinal monitoring of islet cell plasticity in the living organism. In this respect a number of imaging methodologies have been developed over the years for the study of islets in situ in the pancreas, a challenging task due to the relatively small size of the islets and their location, scattered throughout the organ. To increase imaging resolution and allow for longitudinal studies in individual islets, another strategy is based on the transplantation of islets into other sites that are more accessible for imaging. In this review we present the anterior chamber of the eye as a transplantation and imaging site for the study of pancreatic islet cell plasticity, and summarize the major research outcomes facilitated by this technological platform.

Annexin A6 Is Critical to Maintain Glucose Homeostasis and Survival During Liver Regeneration in Mice.

Liver regeneration requires the organized and sequential activation of events that lead to restoration of hepatic mass. During this process, other vital liver functions need to be preserved, such as maintenance of blood glucose homeostasis, balancing the degradation of hepatic glycogen stores, and gluconeogenesis (GNG). Under metabolic stress, alanine is the main hepatic gluconeogenic substrate, and its availability is the rate-limiting step in this pathway. Na+ -coupled neutral amino acid transporters (SNATs) 2 and 4 are believed to facilitate hepatic alanine uptake. In previous studies, we demonstrated that a member of the Ca2+ -dependent phospholipid binding annexins, Annexin A6 (AnxA6), regulates membrane trafficking along endo- and exocytic pathways. Yet, although AnxA6 is abundantly expressed in the liver, its function in hepatic physiology remains unknown. In this study, we investigated the potential contribution of AnxA6 in liver regeneration. Utilizing AnxA6 knockout mice (AnxA6-/- ), we challenged liver function after partial hepatectomy (PHx), inducing acute proliferative and metabolic stress. Biochemical and immunofluorescent approaches were used to dissect AnxA6-/- mice liver proliferation and energetic metabolism. Most strikingly, AnxA6-/- mice exhibited low survival after PHx. This was associated with an irreversible and progressive drop of blood glucose levels. Whereas exogenous glucose administration or restoration of hepatic AnxA6 expression rescued AnxA6-/- mice survival after PHx, the sustained hypoglycemia in partially hepatectomized AnxA6-/- mice was the consequence of an impaired alanine-dependent GNG in AnxA6-/- hepatocytes. Mechanistically, cytoplasmic SNAT4 failed to recycle to the sinusoidal plasma membrane of AnxA6-/- hepatocytes 48hours after PHx, impairing alanine uptake and, consequently, glucose production. We conclude that the lack of AnxA6 compromises alanine-dependent GNG and liver regeneration in mice.

Designing a bioelectronic treatment for Type 1 diabetes: targeted parasympathetic modulation of insulin secretion.

The pancreas is a visceral organ with exocrine functions for digestion and endocrine functions for maintenance of blood glucose homeostasis. In pancreatic diseases such as Type 1 diabetes, islets of the endocrine pancreas become dysfunctional and normal regulation of blood glucose concentration ceases. In healthy individuals, parasympathetic signaling to islets via the vagus nerve, triggers release of insulin from pancreatic β-cells and glucagon from α-cells. Using electrical stimulation to augment parasympathetic signaling may provide a way to control pancreatic endocrine functions and ultimately control blood glucose. Historical data suggest that cervical vagus nerve stimulation recruits many visceral organ systems. Simultaneous modulation of liver and digestive function along with pancreatic function provides differential signals that work to both raise and lower blood glucose. Targeted pancreatic vagus nerve stimulation may provide a solution to minimizing off-target effects through careful electrode placement just prior to pancreatic insertion.

Transcription Factor HMG Box-Containing Protein 1 (HBP1) Regulates Glycemic Homeostasis Through Modulation of Gluconeogenesis

Abstract Objectives Glycemic dysregulation is one of the major metabolic disorders, which has long been a significant public health issue. The liver plays a pivotal role in the maintenance of blood glucose homeostasis. Previous studies indicate that upon refeeding a high carbohydrate diet, the expression of transcription factor HMG box-containing protein 1 (HBP1) was elevated in mice livers, suggesting a role of HBP1 in carbohydrate metabolism. Therefore, the objective of the current study was to understand the molecular mechanisms through which HBP1 regulates glucose generation in the liver. Methods Both in vivo HBP1 knockdown mice and in vitro HepG2 cell line were employed as the experimental models. Results First, we observed that overnight fasting led to increased PEPCK but decreased HBP1 expression in mice livers, and subsequent addition of insulin reversed the expression pattern. More importantly, HBP1 knockout (KO) mice displayed a significantly higher blood glucose level (173 mg/dL) than that of the controls (98 mg/dL). Also, HBP1 KO led to impaired OGTT (oral glucose tolerance test) and ITT (insulin tolerance test). These data suggest that HBP1 might have a role in the regulation of gluconeogenesis in the liver. To unveil the molecular mechanism by which HBP1 regulates glucose homeostasis, we examined its role in gluconeogenesis. Administration of gluconeogenic stimulators glucagon (100 nM) and cAMP (0.5 ng/mL) resulted in increased expression of Phosphoenolpyruvate carboxykinase (PEPCK; encoded by the PCK1 gene), a key enzyme in gluconeogenesis, but decreased HBP1 expression in HepG2 cells. Last, HBP1 siRNA-mediated mRNA disruption led to elevated PEPCK expression, whereas ectopic expression of HBP1 (pcDNA3-HBP1-Flag) significantly suppressed it. Conclusions In conclusion, our data indicate that HBP1 might negatively regulate glucose production and support HBP1 as a novel biological regulator of blood glucose homeostasis. Funding Sources This work was supported by the grant to MOST 108–2320-B-039–051-MY3 C-Y Huang.

Incretin-the new therapeutic target of sepsis

An article entitled Therapeutic Effects of Endogenous Icretin Hormones and Exogenous Incretin-Based Medications in was published in November 2019 in JCEM[Faraaz AS, Hussain M, Teresa GM, et al. J Clin Endocrinol Metab, 2019, 104(11): 5274-5284]. We translated this article into Chinese after obtaining the copyright from the journal. Sepsis is currently defined as a life-threatening organ dysfunction caused by a host′s dysregulation of infection which can increase the risk of organ dysfunction and death if combined with abnormal blood glucose. For that reason, the authors believe that there is a need to find new targets for the treatment of and maintenance of blood glucose homeostasis. Incretin can regulate various functions, including islet hormone secretion, blood glucose concentration, lipid metabolism, intestinal motility, appetite, body weight, immune function, and so on. Nowadays the research on in is still limited. The authors utilized the medical keywords incretin , glucagon-like peptide-1 , gastric inhibitory peptide , and sepsis for Pubmed search in this small retrospective study. The results of preclinical research models and clinical trials suggest that incretin-based therapies can improve immune function, control blood glucose effectively and reduce the incidence and mortality of organ dysfunction. However, the authors believe that further clinical studies are still needed to observe the effects of on sepsis. In summary, there is probably a way to maintain blood glucose homeostasis while reducing inflammation and improving clinical outcomes if the hormone axis in is brought to attention. Key words: Sepsis; Incretin

GSTO1 regulates insulin biosynthesis in pancreatic β cells

Insulin biosynthesis and secretion by pancreatic β cells are critical for the maintenance of blood glucose homeostasis. Here, we show that the expression of glutathione S-transferase omega-1 (GSTO1) is upregulated in the primary islet cells of diabetic Goto-Kakizaki (GK) rats. Knocking out GSTO1 upregulated insulin transcripts and increased the insulin content in both INS-1 cells and primary islet cells. In contrast, overexpression of GSTO1 reduced the insulin content. Furthermore, knocking out GSTO1 increased the expression of pancreatic duodenal homeobox-1 (PDX1) at both the transcription and protein levels. These results indicate that GSTO1 may be involved in the regulation of insulin biosynthesis by modulating the transcriptional expression of PDX1.

Influence of selenium supplementation on carbohydrate metabolism and oxidative stress in pregnant women with gestational diabetes mellitus.

In the presence of conflicting advice about the relationship between selenium-type II diabetes-oxidative stress trio, this study aimed to assess the consequences of selenium supplementation on fasting plasma glucose (FPG) level, antioxidant activities of selenodependent and non-selenodependent enzymes, and other markers of oxidative stress studied for the first time during gestational diabetes mellitus (GDM). This research was carried out among 180 pregnant Algerian women, 60 of whom were in good health, 60 women with GDM did not take supplements, and 60 women with GDM took selenium orally (50 mg/d) for 12 weeks starting from their second trimester of pregnancy. Blood samples were taken in order to assay FPG level and oxidative stress markers. Selenium supplementation during GDM has demonstrated its hypoglycemic power in the significant decline of FPG level, and its antioxidant properties in the significant reinforcement of antioxidant activities of erythrocyte selenodependent enzymes (glutathione peroxidase and glutathione reductase), the significant increase in erythrocyte catalase and superoxide dismutase activities simultaneously with the highest decrease in erythrocyte and plasma malondialdehyde levels. This decrease was only significant for plasma carbonyl proteins, which was not the case for erythrocyte carbonyl proteins. The recourse to selenium supplementation by seleno-deficient pregnant women with GDM is beneficial for maternal health. This micronutrient exploits its antioxidant and insulin-mimetic properties in the maintenance of blood glucose homeostasis and the fight against oxidative stress, and consequently, its supplementation delays the occurrence of GDM complications.

MicroRNAs in islet hormone secretion.

Pancreatic islet hormone secretion is central in the maintenance of blood glucose homeostasis. During development of hyperglycaemia, the β-cell is under pressure to release more insulin to compensate for increased insulin resistance. Failure of the β-cells to secrete enough insulin results in type 2 diabetes (T2D). MicroRNAs (miRNAs) are short non-coding RNA molecules suitable for rapid regulation of the changes in target gene expression needed in β-cell adaptations. Moreover, miRNAs are involved in the maintenance of α-cell and β-cell phenotypic identities via cell-specific, or cell-enriched expression. Although many of the abundant miRNAs are highly expressed in both cell types, recent research has focused on the role of miRNAs in β-cells. It has been shown that highly abundant miRNAs, such as miR-375, are involved in several cellular functions indispensable in maintaining β-cell phenotypic identity, almost acting as "housekeeping genes" in the context of hormone secretion. Despite the abundance and importance of miR-375, it has not been shown to be differentially expressed in T2D islets. On the contrary, the less abundant miRNAs such as miR-212/miR-132, miR-335, miR-130a/b and miR-152 are deregulated in T2D islets, wherein the latter three miRNAs were shown to play key roles in regulating β-cell metabolism. In this review, we focus on β-cell function and describe miRNAs involved in insulin biosynthesis and processing, glucose uptake and metabolism, electrical activity and Ca2+ -influx and exocytosis of the insulin granules. We present current status on miRNA regulation in α-cells, and finally we discuss the involvement of miRNAs in β-cell dysfunction underlying T2D pathogenesis.

Identifying New Regulators of Insulin‐Stimulated GLUT4 Exocytosis

GLUT4 is an insulin responsive glucose transporter responsible for the maintenance of blood glucose homeostasis. At basal conditions GLUT4 is sequestered inside the cell in specialized storage vesicles. After a meal, insulin signaling causes translocation of GLUT4 from these storage vesicles to the plasma membrane where it aids in the removal of glucose from the blood. Misregulation of this system is a major contributor to the global rise in rates of insulin resistance and metabolic disease. While the physiological importance of this pathway is obvious, the underlying molecular mechanisms remain poorly understood. This difficulty in elucidating the pathway is due to several factors, such as the complicated nature of vesicle transport pathways and technical barriers that have existed with using mammalian cells for genetic screens. The advent of CRISPR‐Cas9 genome editing has allowed us to overcome this second obstacle. Many labs have shown its utility in dissecting pathways for cell viability and growth; our lab has adapted it for vesicle trafficking studies. Using the CRISPR‐Cas9 system in conjunction with our trafficking assay, we performed an unbiased genome wide knockout screen to search for previously unknown regulators of this complex and important metabolic pathway. Specifically, the screen was designed to find regulators whose knockout causes a decrease in GLUT4 translocation after insulin stimulation. The screen identified several known regulators of GLUT4 exocytosis, such as RABIF and Rab10, suggesting that the screen was successful. Many of the hits, however, are not known to be involved in the GLUT4 exocytic pathway, such as TRAF3 and ANTRXL.Support or Funding InformationR01 DK095367This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Progresses of the Past Decade on Factors Contributing to Skeletal Muscle Glycogen Synthase Regulation

Glycogen is the primary storage form of glucose, which is metabolized actively in the liver and skeletal muscle of mammals. The skeletal muscle glycogen is used intracellularly to provide starting substrate for glycolysis, whereas liver glycogen is used mainly for the maintenance of blood glucose homeostasis. The conversion of glucose to glycogen is an ordered process, in which the enzyme glycogen synthase plays an essential role. The key events in the synthesis of glycogen have been elucidated in both the liver and muscle. The process of understanding the regulatory mechanism of glycogen synthase activity has led to the discoveries of many important players in cellular metabolism. Research in identifying factors modulating muscle glycogen synthesis has been of popular interest within the past decade. The goal of this review is to summarize potential factors affecting skeletal muscle glycogen synthase expression level and activity in literatures published for the past decade.

DICER Inactivation Identifies Pancreatic β-Cell "Disallowed" Genes Targeted by MicroRNAs.

Pancreatic β-cells are the body's sole source of circulating insulin and essential for the maintenance of blood glucose homeostasis. Levels of up to 66 “disallowed” genes, which are strongly expressed and play housekeeping roles in most other mammalian tissues, are unusually low in β-cells. The molecular mechanisms involved in repressing these genes are largely unknown. Here, we explore the role in gene disallowance of microRNAs (miRNAs), a type of small noncoding RNAs that silence gene expression at the posttranscriptional level and are essential for β-cell development and function. To selectively deplete miRNAs from adult β-cells, the miRNA-processing enzyme DICER was inactivated by deletion of the RNase III domain with a tamoxifen-inducible Pdx1CreER transgene. In this model, β-cell dysfunction was apparent 2 weeks after recombination and preceded a decrease in insulin content and loss of β-cell mass. Of the 14 disallowed genes studied, quantitative RT-quantitative real-time PCR revealed that 6 genes (Fcgrt, Igfbp4, Maf, Oat, Pdgfra, and Slc16a1) were up-regulated (1.4- to 2.1-fold, P < .05) at this early stage. Expression of luciferase constructs bearing the 3′-untranslated regions of the corresponding mRNAs in wild-type or DICER-null β-cells demonstrated that Fcgrt, Oat, and Pdgfra are miRNA direct targets. We thus reveal a role for miRNAs in the regulation of disallowed genes in β-cells and provide evidence for a novel means through which noncoding RNAs control the functional identity of these cells independently of actions on β-cell mass.

Light scattering as an intrinsic indicator for pancreatic islet cell mass and secretion.

The pancreatic islet of Langerhans is composed of endocrine cells producing and releasing hormones from secretory granules in response to various stimuli for maintenance of blood glucose homeostasis. In order to adapt to a variation in functional demands, these islets are capable of modulating their hormone secretion by increasing the number of endocrine cells as well as the functional response of individual cells. A failure in adaptive mechanisms will lead to inadequate blood glucose regulation and thereby to the development of diabetes. It is therefore necessary to develop tools for the assessment of both pancreatic islet mass and function, with the aim of understanding cellular regulatory mechanisms and factors guiding islet plasticity. Although most of the existing techniques rely on the use of artificial indicators, we present an imaging methodology based on intrinsic optical properties originating from mature insulin secretory granules within endocrine cells that reveals both pancreatic islet mass and function. We demonstrate the advantage of using this imaging strategy by monitoring in vivo scattering signal from pancreatic islets engrafted into the anterior chamber of the mouse eye, and how this versatile and noninvasive methodology permits the characterization of islet morphology and plasticity as well as hormone secretory status.

Identification of particular groups of microRNAs that positively or negatively impact on beta cell function in obese models of type 2 diabetes

MicroRNAs are key regulators of gene expression involved in health and disease. The goal of our study was to investigate the global changes in beta cell microRNA expression occurring in two models of obesity-associated type 2 diabetes and to assess their potential contribution to the development of the disease. MicroRNA profiling of pancreatic islets isolated from prediabetic and diabetic db/db mice and from mice fed a high-fat diet was performed by microarray. The functional impact of the changes in microRNA expression was assessed by reproducing them in vitro in primary rat and human beta cells. MicroRNAs differentially expressed in both models of obesity-associated type 2 diabetes fall into two distinct categories. A group including miR-132, miR-184 and miR-338-3p displays expression changes occurring long before the onset of diabetes. Functional studies indicate that these expression changes have positive effects on beta cell activities and mass. In contrast, modifications in the levels of miR-34a, miR-146a, miR-199a-3p, miR-203, miR-210 and miR-383 primarily occur in diabetic mice and result in increased beta cell apoptosis. These results indicate that obesity and insulin resistance trigger adaptations in the levels of particular microRNAs to allow sustained beta cell function, and that additional microRNA deregulation negatively impacting on insulin-secreting cells may cause beta cell demise and diabetes manifestation. We propose that maintenance of blood glucose homeostasis or progression toward glucose intolerance and type 2 diabetes may be determined by the balance between expression changes of particular microRNAs.

Models for the Study of Whole-Body Glucose Kinetics: A Mathematical Synthesis

The maintenance of blood glucose homeostasis is complex and involves several key tissues. Most of these tissues are not easily accessible, making direct measurement of the physiological parameters involved in glucose metabolism difficult. The use of isotope tracer methodology and mathematical modeling allows indirect estimates ofin vivoglucose metabolism through relatively noninvasive means. The purpose of this paper was to provide a mathematical synthesis of the models developed for describing glucose kinetics. As many of the models were developed using dogs, example data from the canine literature are presented. However, examples from the human and feline literature are also given in the absence of dog data. The glucose system is considered in both the steady and nonsteady states, and the models are examined by grouping them into schemes consisting of one, two, and three glucose compartments. Noncompartmental schemes are also considered briefly.