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1.
Clin Nutr ; 36(2): 355-363, 2017 04.
Article in English | MEDLINE | ID: mdl-27686693

ABSTRACT

Growing evidence underscores the important role of glycemic control in health and recovery from illness. Carbohydrate ingestion in the diet or administration in nutritional support is mandatory, but carbohydrate intake can adversely affect major body organs and tissues if resulting plasma glucose becomes too high, too low, or highly variable. Plasma glucose control is especially important for patients with conditions such as diabetes or metabolic stress resulting from critical illness or surgery. These patients are particularly in need of glycemic management to help lessen glycemic variability and its negative health consequences when nutritional support is administered. Here we report on recent findings and emerging trends in the field based on an ESPEN workshop held in Venice, Italy, 8-9 November 2015. Evidence was discussed on pathophysiology, clinical impact, and nutritional recommendations for carbohydrate utilization and management in nutritional support. The main conclusions were: a) excess glucose and fructose availability may exacerbate metabolic complications in skeletal muscle, adipose tissue, and liver and can result in negative clinical impact; b) low-glycemic index and high-fiber diets, including specialty products for nutritional support, may provide metabolic and clinical benefits in individuals with obesity, insulin resistance, and diabetes; c) in acute conditions such as surgery and critical illness, insulin resistance and elevated circulating glucose levels have a negative impact on patient outcomes and should be prevented through nutritional and/or pharmacological intervention. In such acute settings, efforts should be implemented towards defining optimal plasma glucose targets, avoiding excessive plasma glucose variability, and optimizing glucose control relative to nutritional support.


Subject(s)
Dietary Carbohydrates/administration & dosage , Dietary Carbohydrates/adverse effects , Insulin Resistance , Nutrition Policy , Nutritional Support , Blood Glucose/metabolism , Carbohydrate Metabolism , Diet , Evidence-Based Medicine , Glycemic Index , Humans , Hyperglycemia/etiology , Hyperglycemia/therapy , Hypoglycemia/etiology , Hypoglycemia/therapy , Italy , Nutritional Requirements , Risk Factors , Societies, Scientific
3.
Osteoporos Int ; 26(1): 209-18, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25127672

ABSTRACT

UNLABELLED: A role for gut hormone in bone physiology has been suspected. We evidenced alterations of microstructural morphology (trabecular and cortical) and bone strength (both at the whole-bone--and tissue-level) in double incretin receptor knock-out (DIRKO) mice as compared to wild-type littermates. These results support a role for gut hormones in bone physiology. INTRODUCTION: The two incretins, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), have been shown to control bone remodeling and strength. However, lessons from single incretin receptor knock-out mice highlighted a compensatory mechanism induced by elevated sensitivity to the other gut hormone. As such, it is unclear whether the bone alterations observed in GIP or GLP-1 receptor deficient animals resulted from the lack of a functional gut hormone receptor, or by higher sensitivity for the other gut hormone. The aims of the present study were to investigate the bone microstructural morphology, as well as bone tissue properties, in double incretin receptor knock-out (DIRKO) mice. METHODS: Twenty-six-week-old DIRKO mice were age- and sex-matched with wild-type (WT) littermates. Bone microstructural morphology was assessed at the femur by microCT and quantitative X-ray imaging, while tissue properties were investigated by quantitative backscattered electron imaging and Fourier-transformed infrared microscopy. Bone mechanical response was assessed at the whole-bone- and tissue-level by 3-point bending and nanoindentation, respectively. RESULTS: As compared to WT animals, DIRKO mice presented significant augmentations in trabecular bone mass and trabecular number whereas bone outer diameter, cortical thickness, and cortical area were reduced. At the whole-bone-level, yield stress, ultimate stress, and post-yield work to fracture were significantly reduced in DIRKO animals. At the tissue-level, only collagen maturity was reduced by 9 % in DIRKO mice leading to reductions in maximum load, hardness, and dissipated energy. CONCLUSIONS: This study demonstrated the critical role of gut hormones in controlling bone microstructural morphology and tissue properties.


Subject(s)
Femur/pathology , Gastric Inhibitory Polypeptide/physiology , Glucagon-Like Peptide 1/physiology , Adolescent , Animals , Biomechanical Phenomena/physiology , Bone Density/physiology , Femur/physiopathology , Gastric Inhibitory Polypeptide/deficiency , Gastric Inhibitory Polypeptide/genetics , Glucagon-Like Peptide 1/deficiency , Glucagon-Like Peptide 1/genetics , Glucose Intolerance/physiopathology , Glucose Tolerance Test/methods , Humans , Mice, Knockout , Stress, Mechanical , X-Ray Microtomography/methods
5.
Diabetes Obes Metab ; 16 Suppl 1: 87-95, 2014 Sep.
Article in English | MEDLINE | ID: mdl-25200301

ABSTRACT

Intracellular glucose signalling pathways control the secretion of glucagon and insulin by pancreatic islet α- and ß-cells, respectively. However, glucose also indirectly controls the secretion of these hormones through regulation of the autonomic nervous system that richly innervates this endocrine organ. Both parasympathetic and sympathetic nervous systems also impact endocrine pancreas postnatal development and plasticity in adult animals. Defects in these autonomic regulations impair ß-cell mass expansion during the weaning period and ß-cell mass adaptation in adult life. Both branches of the autonomic nervous system also regulate glucagon secretion. In type 2 diabetes, impaired glucose-dependent autonomic activity causes the loss of cephalic and first phases of insulin secretion, and impaired suppression of glucagon secretion in the postabsorptive phase; in diabetic patients treated with insulin, it causes a progressive failure of hypoglycaemia to trigger the secretion of glucagon and other counterregulatory hormones. Therefore, identification of the glucose-sensing cells that control the autonomic innervation of the endocrine pancreatic and insulin and glucagon secretion is an important goal of research. This is required for a better understanding of the physiological control of glucose homeostasis and its deregulation in diabetes. This review will discuss recent advances in this field of investigation.


Subject(s)
Feedback, Physiological , Islets of Langerhans/innervation , Models, Biological , Neurons/physiology , Parasympathetic Nervous System/physiology , Sympathetic Nervous System/physiology , Animals , Appetite Regulation , Cell Size , Diabetes Mellitus/metabolism , Diabetes Mellitus/pathology , Diabetes Mellitus/physiopathology , Glucagon/metabolism , Glucagon-Secreting Cells/cytology , Glucagon-Secreting Cells/metabolism , Glucagon-Secreting Cells/pathology , Glucose Transporter Type 2/metabolism , Humans , Islets of Langerhans/cytology , Islets of Langerhans/metabolism , Islets of Langerhans/pathology , Nerve Tissue Proteins/metabolism , Neurons/pathology , Parasympathetic Nervous System/cytology , Parasympathetic Nervous System/pathology , Parasympathetic Nervous System/physiopathology , Solitary Nucleus/physiology , Solitary Nucleus/physiopathology , Sympathetic Nervous System/cytology , Sympathetic Nervous System/pathology , Sympathetic Nervous System/physiopathology
7.
J Intern Med ; 274(3): 203-14, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23751050

ABSTRACT

In healthy individuals, insulin resistance is associated with physiological conditions such as pregnancy or body weight gain and triggers an increase in beta cell number and insulin secretion capacity to preserve normoglycaemia. Failure of this beta cell compensation capacity is a fundamental cause of diabetic hyperglycaemia. Incomplete understanding of the molecular mechanisms controlling the plasticity of adult beta cells mechanisms and how these cells fail during the pathogenesis of diabetes strongly limits the ability to develop new beta cell-specific therapies. Here, current knowledge of the signalling pathways controlling beta cell plasticity is reviewed, and possible directions for future research are discussed.


Subject(s)
Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/physiopathology , Diabetes Mellitus, Type 2/therapy , Glucose/metabolism , Insulin Resistance/physiology , Insulin-Secreting Cells/metabolism , Insulin/metabolism , Animals , Cell Differentiation/physiology , Disease Progression , Female , Gastrointestinal Hormones/metabolism , Humans , Hyperglycemia/metabolism , Hyperglycemia/physiopathology , Hyperglycemia/therapy , Insulin Secretion , Male , Pregnancy , Risk Factors , Signal Transduction
8.
Diabetes Metab ; 39(2): 89-93, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23523140

ABSTRACT

Glucagon-like peptide (GLP)-1 action involves both endocrine and neural pathways to control peripheral tissues. In diabetes the impairment of either pathway may define different subsets of patients: some may be better treated with GLP-1 receptor agonists that are more likely to directly stimulate beta-cells and extrapancreatic receptors, while others may benefit from dipeptidyl peptidase (DPP)-4 inhibitor treatments that are more likely to increase the neural gut-brain-pancreas axis. Elevated plasma concentrations of GLP-1 associated with agonist treatment or bariatric surgery also appear to exert neuroprotective effects, ameliorate postprandial and fasting lipids, improve heart physiology and protect against heart failure, thereby expanding the possible positioning of GLP-1-based therapies. However, the mechanisms behind GLP-1 secretion, the role played by proximal and distal intestinal GLP-1-producing cells as well as the molecular basis of GLP-1 resistance in diabetes are still to be ascertained. The pharmacological features distinguishing GLP-1 receptor agonists from DPP-4 inhibitors are discussed here to address their respective positions in type 2 diabetes.


Subject(s)
Cardiovascular Diseases/drug therapy , Diabetes Mellitus, Type 2/drug therapy , Diabetic Angiopathies/drug therapy , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Glucagon-Like Peptide 1/metabolism , Incretins/metabolism , Bariatric Surgery/trends , Cardiovascular Diseases/blood , Cardiovascular Diseases/prevention & control , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/complications , Diabetic Angiopathies/blood , Diabetic Angiopathies/prevention & control , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Fasting , Female , Glucagon-Like Peptide 1/pharmacology , Glucagon-Like Peptide 1/therapeutic use , Humans , Incretins/pharmacology , Incretins/therapeutic use , Lipids/blood , Male
9.
Diabetes Obes Metab ; 13 Suppl 1: 82-8, 2011 Oct.
Article in English | MEDLINE | ID: mdl-21824260

ABSTRACT

Glucose homeostasis requires the tight regulation of glucose utilization by liver, muscle and white or brown fat, and glucose production and release in the blood by liver. The major goal of maintaining glycemia at ∼ 5 mM is to ensure a sufficient flux of glucose to the brain, which depends mostly on this nutrient as a source of metabolic energy. This homeostatic process is controlled by hormones, mainly glucagon and insulin, and by autonomic nervous activities that control the metabolic state of liver, muscle and fat tissue but also the secretory activity of the endocrine pancreas. Activation or inhibition of the sympathetic or parasympathetic branches of the autonomic nervous systems are controlled by glucose-excited or glucose-inhibited neurons located at different anatomical sites, mainly in the brainstem and the hypothalamus. Activation of these neurons by hyper- or hypoglycemia represents a critical aspect of the control of glucose homeostasis, and loss of glucose sensing by these cells as well as by pancreatic ß-cells is a hallmark of type 2 diabetes. In this article, aspects of the brain-endocrine pancreas axis are reviewed, highlighting the importance of central glucose sensing in the control of counterregulation to hypoglycemia but also mentioning the role of the neural control in ß-cell mass and function. Overall, the conclusions of these studies is that impaired glucose homeostasis, such as associated with type 2 diabetes, but also defective counterregulation to hypoglycemia, may be caused by initial defects in glucose sensing.


Subject(s)
Autonomic Nervous System/metabolism , Blood Glucose/metabolism , Brain/metabolism , Diabetes Mellitus, Type 2/metabolism , Glucagon/metabolism , Glucose Transporter Type 2/metabolism , Insulin/metabolism , Autonomic Nervous System/physiology , Biological Transport , Diabetes Mellitus, Type 2/physiopathology , Homeostasis , Humans , Hyperglycemia/metabolism , Hypoglycemia/metabolism , Insulin Secretion , Islets of Langerhans/metabolism , Signal Transduction
10.
Diabetes Metab ; 36 Suppl 3: S45-9, 2010 Oct.
Article in English | MEDLINE | ID: mdl-21211735

ABSTRACT

A large body of data gathered over the last decades has delineated the neuronal pathways that link the central nervous system with the autonomic innervation of the endocrine pancreas, which controls alpha- and beta-cell secretion activity and mass. These are important regulatory functions that are certainly keys for preserving the capacity of the endocrine pancreas to control glucose homeostasis over a lifetime. Identifying the cells involved in controlling the autonomic innervation of the endocrine pancreas, in response to nutrient, hormonal and environmental cues and how these cues are detected to activate neuronal activity are important goals of current research. Elucidation of these questions may possibly lead to new means for preserving or restoring defects in insulin and glucagon secretion associated with type 2 diabetes.


Subject(s)
Autonomic Nervous System/physiology , Brain Stem/metabolism , Glucose/metabolism , Insulin-Secreting Cells/metabolism , Animals , Glucagon/metabolism , Homeostasis , Insulin/metabolism , Mice
11.
Diabetologia ; 52(10): 2159-68, 2009 Oct.
Article in English | MEDLINE | ID: mdl-19644669

ABSTRACT

AIMS/HYPOTHESIS: High- vs low-glycaemic index (GI) diets unfavourably affect body fat mass and metabolic markers in rodents. Different effects of these diets could be age-dependent, as well as mediated, in part, by carbohydrate-induced stimulation of glucose-dependent insulinotrophic polypeptide (GIP) signalling. METHODS: Young-adult (16 weeks) and aged (44 weeks) male wild-type (C57BL/6J) and GIP-receptor knockout (Gipr ( -/- )) mice were exposed to otherwise identical high-carbohydrate diets differing only in GI (20-26 weeks of intervention, n = 8-10 per group). Diet-induced changes in body fat distribution, liver fat, locomotor activity, markers of insulin sensitivity and substrate oxidation were investigated, as well as changes in the gene expression of anorexigenic and orexigenic hypothalamic factors related to food intake. RESULTS: Body weight significantly increased in young-adult high- vs low-GI fed mice (two-way ANOVA, p < 0.001), regardless of the Gipr genotype. The high-GI diet in young-adult mice also led to significantly increased fat mass and changes in metabolic markers that indicate reduced insulin sensitivity. Even though body fat mass also slightly increased in high- vs low-GI fed aged wild-type mice (p < 0.05), there were no significant changes in body weight and estimated insulin sensitivity in these animals. However, aged Gipr ( -/- ) vs wild-type mice on high-GI diet showed significantly lower cumulative net energy intake, increased locomotor activity and improved markers of insulin sensitivity. CONCLUSIONS/INTERPRETATION: The metabolic benefits of a low-GI diet appear to be more pronounced in younger animals, regardless of the Gipr genotype. Inactivation of GIP signalling in aged animals on a high-GI diet, however, could be beneficial.


Subject(s)
Diet , Gastric Inhibitory Polypeptide/physiology , Glycemic Index , Age Factors , Animals , Blood Glucose/analysis , Body Composition , Calorimetry , Energy Intake/physiology , Glucose Tolerance Test , Insulin/blood , Male , Mice , Mice, Knockout , Receptors, Gastrointestinal Hormone/genetics , Receptors, Gastrointestinal Hormone/physiology , Reverse Transcriptase Polymerase Chain Reaction , Triglycerides/metabolism
12.
Int J Obes (Lond) ; 32 Suppl 6: S62-71, 2008 Dec.
Article in English | MEDLINE | ID: mdl-19079282

ABSTRACT

The control of body weight and of blood glucose concentrations depends on the exquisite coordination of the function of several organs and tissues, in particular the liver, muscle and fat. These organs and tissues have major roles in the use and storage of nutrients in the form of glycogen or triglycerides and in the release of glucose or free fatty acids into the blood, in periods of metabolic needs. These mechanisms are tightly regulated by hormonal and nervous signals, which are generated by specialized cells that detect variations in blood glucose or lipid concentrations. The hormones insulin and glucagon not only regulate glycemic levels through their action on these organs and the sympathetic and parasympathetic branches of the autonomic nervous system, which are activated by glucose or lipid sensors, but also modulate pancreatic hormone secretion and liver, muscle and fat glucose and lipid metabolism. Other signaling molecules, such as the adipocyte hormones leptin and adiponectin, have circulating plasma concentrations that reflect the level of fat stored in adipocytes. These signals are integrated at the level of the hypothalamus by the melanocortin pathway, which produces orexigenic and anorexigenic neuropeptides to control feeding behavior, energy expenditure and glucose homeostasis. Work from several laboratories, including ours, has explored the physiological role of glucose as a signal that regulates these homeostatic processes and has tested the hypothesis that the mechanism of glucose sensing that controls insulin secretion by the pancreatic beta-cells is also used by other cell types. I discuss here evidence for these mechanisms, how they integrate signals from other nutrients such as lipids and how their deregulation may initiate metabolic diseases.


Subject(s)
Blood Glucose/metabolism , Diabetes Mellitus, Type 2/etiology , Glucagon/metabolism , Insulin/metabolism , Obesity/etiology , Animals , Appetite Regulation/physiology , Brain/metabolism , Diabetes Mellitus, Type 2/metabolism , Fatty Acids/metabolism , Mice , Obesity/metabolism , Pancreas/metabolism , Portal System/metabolism , Rats
13.
Diabetologia ; 50(3): 682-9, 2007 Mar.
Article in English | MEDLINE | ID: mdl-17235524

ABSTRACT

AIMS/HYPOTHESIS: Excess glucose transport to embryos during diabetic pregnancy causes congenital malformations. The early postimplantation embryo expresses the gene encoding the high-Km GLUT2 (also known as SLC2A2) glucose transporter. The hypothesis tested here is that high-Km glucose transport by GLUT2 causes malformations resulting from maternal hyperglycaemia during diabetic pregnancy. MATERIALS AND METHODS: Glut2 mRNA was assayed by RT-PCR. The Km of embryo glucose transport was determined by measuring 0.5-20 mmol/l 2-deoxy[3H]glucose transport. To test whether the GLUT2 transporter is required for neural tube defects resulting from maternal hyperglycaemia, Glut2+/- mice were crossed and transient hyperglycaemia was induced by glucose injection on day 7.5 of pregnancy. Embryos were recovered on day 10.5, and the incidence of neural tube defects in wild-type, Glut2+/- and Glut2-/- embryos was scored. RESULTS: Early postimplantation embryos expressed Glut2, and expression was unaffected by maternal diabetes. Moreover, glucose transport by these embryos showed Michaelis-Menten kinetics of 16.19 mmol/l, consistent with transport mediated by GLUT2. In pregnancies made hyperglycaemic on day 7.5, neural tube defects were significantly increased in wild-type embryos, but Glut2+/- embryos were partially protected from neural tube defects, and Glut2-/- embryos were completely protected from these defects. The frequency of occurrence of wild-type, Glut2+/- and Glut2-/- embryos suggests that the presence of Glut2 alleles confers a survival advantage in embryos before day 10.5. CONCLUSIONS/INTERPRETATIONS: High-Km glucose transport by the GLUT2 glucose transporter during organogenesis is responsible for the embryopathic effects of maternal diabetes.


Subject(s)
Diabetes Mellitus/genetics , Gene Expression Regulation, Developmental , Glucose Transporter Type 2/genetics , Neural Tube Defects/genetics , Animals , Biological Transport , Crosses, Genetic , Deoxyglucose/metabolism , Embryonic Development , Female , Glucose Transporter Type 2/metabolism , Kinetics , Male , Mice , Pregnancy , RNA, Messenger/genetics , Reverse Transcriptase Polymerase Chain Reaction
17.
Horm Metab Res ; 36(11-12): 766-70, 2004.
Article in English | MEDLINE | ID: mdl-15655706

ABSTRACT

GLP-1 has both peripheral and central actions, as this hormone is secreted by gut endocrine cells and brainstem neurons projecting into the hypothalamus and other brain regions. GLP-1 has multiple regulatory functions participating in the control of glucose homeostasis, beta-cell proliferation and differentiation, food intake, heart rate and even learning. GLP-1 action depends on binding to a specific G-coupled receptor linked to activation of the adenylyl cyclase pathway. Analysis of mice with inactivation of the GLP-1 receptor gene has provided evidence that absence of GLP-1 action in the mouse, despite this hormone potent physiological effects when administered in vivo, only leads to mild abnormalities in glucose homeostasis without any change in body weight. However, a critical role for this hormone and its receptor was demonstrated in the function of the hepatoportal vein glucose sensor, in contrast to that of the pancreatic beta-cells, although absence of both GLP-1 and GIP receptors leads to a more severe phenotype characterized by a beta-cell-autonomous defect in glucose-stimulated insulin secretion. Together, the studies of these glucoincretin receptor knockout mice provide evidence that these hormones are part of complex regulatory systems where multiple redundant signals are involved.


Subject(s)
Glucagon/physiology , Islets of Langerhans/physiology , Peptide Fragments/physiology , Protein Precursors/physiology , Receptors, Glucagon/physiology , Animals , Body Weight/physiology , Eating/physiology , Glucagon-Like Peptide 1 , Glucagon-Like Peptide-1 Receptor , Heart Rate/physiology , Learning/physiology , Liver/metabolism , Mice , Mice, Knockout , Receptors, Glucagon/deficiency
18.
Cytokine ; 24(1-2): 13-24, 2003 Oct.
Article in English | MEDLINE | ID: mdl-14561487

ABSTRACT

The stress-activated protein kinase c-Jun NH2-terminal kinase (JNK) is a central signal for interleukin-1beta (IL-1beta)-induced apoptosis in insulin-producing beta-cells. The cell-permeable peptide inhibitor of JNK (JNKI1), that introduces the JNK binding domain (JBD) of the scaffold protein islet-brain 1 (IB1) inside cells, effectively prevents beta-cell death caused by this cytokine. To define the molecular targets of JNK involved in cytokine-induced beta-cell apoptosis we investigated whether JNKI1 or stable expression of JBD affected the expression of selected pro- and anti-apoptotic genes induced in rat (RIN-5AH-T2B) and mouse (betaTC3) insulinoma cells exposed to IL-1beta. Inhibition of JNK significantly reduced phosphorylation of the specific JNK substrate c-Jun (p<0.05), IL-1beta-induced apoptosis (p<0.001), and IL-1beta-mediated c-fos gene expression. However, neither JNKI1 nor JBD did influence IL-1beta-induced NO synthesis or iNOS expression or the transcription of the genes encoding mitochondrial manganese superoxide dismutase (MnSOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase rho (GSTrho), heat shock protein (HSP) 70, IL-1beta-converting enzyme (ICE), caspase-3, apoptosis-inducing factor (AIF), Bcl-2 or Bcl-xL. We suggest that the anti-apoptotic effect of JNK inhibition by JBD is independent of the transcription of major pro- and anti-apoptotic genes, but may be exerted at the translational or posttranslational level.


Subject(s)
Adaptor Proteins, Signal Transducing , Apoptosis/physiology , Islets of Langerhans/metabolism , Mitogen-Activated Protein Kinases/metabolism , Nuclear Proteins/metabolism , Trans-Activators/metabolism , Animals , Binding Sites , Insulin/metabolism , Interleukin-1/metabolism , JNK Mitogen-Activated Protein Kinases , Mice , Nitric Oxide , Nitric Oxide Synthase/metabolism , Protein Structure, Tertiary , Rats
19.
J Physiol ; 552(Pt 3): 823-32, 2003 Nov 01.
Article in English | MEDLINE | ID: mdl-12937289

ABSTRACT

The physiological significance of the presence of GLUT2 at the food-facing pole of intestinal cells is addressed by a study of fructose absorption in GLUT2-null and control mice submitted to different sugar diets. Confocal microscopy localization, protein and mRNA abundance, as well as tissue and membrane vesicle uptakes of fructose were assayed. GLUT2 was located in the basolateral membrane of mice fed a meal devoid of sugar or containing complex carbohydrates. In addition, the ingestion of a simple sugar meal promoted the massive recruitment of GLUT2 to the food-facing membrane. Fructose uptake in brush-border membrane vesicles from GLUT2-null mice was half that of wild-type mice and was similar to the cytochalasin B-insensitive component, i.e. GLUT5-mediated uptake. A 5 day consumption of sugar-rich diets increased fructose uptake fivefold in wild-type tissue rings when it only doubled in GLUT2-null tissue. GLUT5 was estimated to contribute to 100 % of total uptake in wild-type mice fed low-sugar diets, falling to 60 and 40 % with glucose and fructose diets respectively; the complement was ensured by GLUT2 activity. The results indicate that basal sugar uptake is mediated by the resident food-facing SGLT1 and GLUT5 transporters, whose mRNA abundances double in long-term dietary adaptation. We also observe that a large improvement of intestinal absorption is promoted by the transient recruitment of food-facing GLUT2, induced by the ingestion of a simple-sugar meal. Thus, GLUT2 and GLUT5 could exert complementary roles in adapting the absorption capacity of the intestine to occasional or repeated loads of dietary sugars.


Subject(s)
Cell Membrane/metabolism , Dietary Sucrose/pharmacology , Enterocytes/metabolism , Fructose/pharmacokinetics , Intestinal Absorption , Monosaccharide Transport Proteins/metabolism , Animals , Fructose/administration & dosage , Glucose/administration & dosage , Glucose Transporter Type 2 , Glucose Transporter Type 5 , Intestinal Mucosa/metabolism , Membrane Glycoproteins/metabolism , Mice , Mice, Knockout , Microvilli/metabolism , Monosaccharide Transport Proteins/genetics , Sodium-Glucose Transporter 1 , Tissue Distribution
20.
Diabetologia ; 46(4): 504-10, 2003 Apr.
Article in English | MEDLINE | ID: mdl-12739022

ABSTRACT

AIMS/HYPOTHESIS: betaTC-tet (H2(k)) is a conditional insulinoma cell line derived from transgenic mice expressing a tetracycline-regulated oncogene. Transgenic expression of several proteins implicated in the apoptotic pathways increase the resistance of betaTC-tet cells in vitro. We tested in vivo the sensitivity of the cells to rejection and the protective effect of genetic alterations in NOD mice. METHODS: betaTC-tet cells and genetically engineered lines expressing Bcl-2 (CDM3D), a dominant negative mutant of MyD88 or SOCS-1 were transplanted in diabetic female NOD mice or in male NOD mice with diabetes induced by high-dose streptozotocin. Survival of functional cell grafts in NOD-scid mice was also analyzed after transfer of splenocytes from diabetic NOD mice. Autoreactive T-cell hybridomas and splenocytes from diabetic NOD mice were stimulated by betaTC-tet cells. RESULTS: betaTC-tet cells and genetically engineered cell lines were all similarly rejected in diabetic NOD mice and in NOD-scid mice after splenocyte transfer. In 3- to 6-week-old male NOD mice treated with high-dose streptozotocin, the cells temporarily survived, in contrast with C57BL/6 mice treated with high-dose streptozotocin (indefinite survival) and untreated 3- to 6-week-old male NOD mice (rejection). The protective effect of high-dose streptozotocin was lost in older male NOD mice. betaTC-tet cells did not stimulate autoreactive T-cell hybridomas, but induced IL-2 secretion by splenocytes from diabetic NOD mice. CONCLUSION/INTERPRETATION: The autoimmune process seems to play an important role in the destruction of betaTC-tet cells in NOD mice. Genetic manipulations intended at increasing the resistance of beta cells were inefficient. Similar approaches should be tested in vivo as well as in vitro. High dose streptozotocin influences immune rejection and should be used with caution.


Subject(s)
Autoimmunity/immunology , Cell Line, Tumor , Insulinoma/immunology , Mice, Inbred NOD/immunology , Animals , Diabetes Mellitus, Experimental/immunology , Diabetes Mellitus, Experimental/metabolism , Female , Graft Rejection/immunology , Graft Survival/immunology , Hybridomas/metabolism , Insulinoma/metabolism , Interleukin-2/pharmacokinetics , Mice , Mice, Inbred C57BL , Spleen/metabolism , Transplants
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