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1.
J Diabetes Res ; 2014: 354094, 2014.
Article in English | MEDLINE | ID: mdl-25133191

ABSTRACT

Diabetic retinopathy (DR) is the leading cause of blindness among the American working population. The purpose of this study is to establish a new diabetic animal model using a cone-dominant avian species to address the distorted color vision and altered cone pathway responses in prediabetic and early diabetic patients. Chicken embryos were injected with either streptozotocin (STZ), high concentration of glucose (high-glucose), or vehicle at embryonic day 11. Cataracts occurred in varying degrees in both STZ- and high glucose-induced diabetic chick embryos at E18. Streptozotocin-diabetic chicken embryos had decreased levels of blood insulin, glucose transporter 4 (Glut4), and phosphorylated protein kinase B (pAKT). In STZ-injected E20 embryos, the ERG amplitudes of both a- and b-waves were significantly decreased, the implicit time of the a-wave was delayed, while that of the b-wave was significantly increased. Photoreceptors cultured from STZ-injected E18 embryos had a significant decrease in L-type voltage-gated calcium channel (L-VGCC) currents, which was reflected in the decreased level of L-VGCCα1D subunit in the STZ-diabetic retinas. Through these independent lines of evidence, STZ-injection was able to induce pathological conditions in the chicken embryonic retina, and it is promising to use chickens as a potential new animal model for type I diabetes.


Subject(s)
Diabetes Mellitus, Experimental/embryology , Diabetes Mellitus, Type 1/embryology , Diabetic Retinopathy/embryology , Prediabetic State/embryology , Animals , Blood Glucose/metabolism , Calcium Channels, L-Type/metabolism , Cataract/blood , Cataract/chemically induced , Cataract/embryology , Chick Embryo , Color Vision , Diabetes Mellitus, Experimental/blood , Diabetes Mellitus, Experimental/chemically induced , Diabetes Mellitus, Type 1/blood , Diabetes Mellitus, Type 1/chemically induced , Diabetic Retinopathy/blood , Diabetic Retinopathy/chemically induced , Diabetic Retinopathy/physiopathology , Embryo Culture Techniques , Glucose , Glucose Transporter Type 4/metabolism , Insulin/blood , Phosphorylation , Prediabetic State/blood , Prediabetic State/chemically induced , Proto-Oncogene Proteins c-akt/metabolism , Retinal Cone Photoreceptor Cells/metabolism , Retinal Cone Photoreceptor Cells/pathology , Streptozocin , Time Factors
2.
Diabetes Technol Ther ; 14(3): 210-7, 2012 Mar.
Article in English | MEDLINE | ID: mdl-22023376

ABSTRACT

BACKGROUND: In the development of glucose control algorithms, mathematical models of glucose metabolism are useful for conducting simulation studies and making real-time predictions upon which control calculations can be based. To obtain type 1 diabetes (T1D) data for the modeling of glucose metabolism, we designed and conducted a clinical study. METHODS: Patients with insulin pump-treated T1D were recruited to perform everyday life events on two separate days. During the study, patients wore their insulin pumps and, in addition, a continuous glucose monitor and an activity monitor to estimate energy expenditure. The sequence of everyday life events was predetermined and included carbohydrate intake, insulin boluses, and bouts of exercise; the events were introduced, temporally separated, in different orders and in different quantities. Throughout the study day, 10-min plasma glucose measurements were taken, and samples for plasma insulin and glucagon analyses were obtained every 10 min for the first 30 min after an event and subsequently every 30 min. RESULTS: We included 12 patients with T1D (75% female, 34.3±9.1 years old [mean±SD], hemoglobin A1c 6.7±0.4%). During the 24 study days we collected information-rich, high-quality data during fast and slow changes in plasma glucose following carbohydrate intake, exercise, and insulin boluses. CONCLUSIONS: This study has generated T1D data suitable for glucose modeling, which will be used in the development of glucose control strategies. Furthermore, the study has given new physiologic insight into the metabolic effects of carbohydrate intake, insulin boluses, and exercise in continuous subcutaneous insulin infusion-treated patients with T1D.


Subject(s)
Blood Glucose/metabolism , Diabetes Mellitus, Type 1/blood , Glucagon/blood , Hypoglycemic Agents/blood , Insulin Infusion Systems , Insulin/blood , Activities of Daily Living , Adult , Denmark , Diabetes Mellitus, Type 1/drug therapy , Diabetes Mellitus, Type 1/embryology , Dietary Carbohydrates/administration & dosage , Dietary Carbohydrates/blood , Exercise Test , Female , Glycated Hemoglobin/metabolism , Heart Rate , Humans , Hypoglycemic Agents/administration & dosage , Infusions, Subcutaneous , Insulin/administration & dosage , Male , Middle Aged , Models, Theoretical
3.
Dis Model Mech ; 3(9-10): 567-80, 2010.
Article in English | MEDLINE | ID: mdl-20616094

ABSTRACT

Diabetes is characterized by the loss, or gradual dysfunction, of insulin-producing pancreatic beta-cells. Although beta-cells can replicate in younger adults, the available diabetes therapies do not specifically target beta-cell regeneration. Novel approaches are needed to discover new therapeutics and to understand the contributions of endocrine progenitors and beta-cell regeneration during islet expansion. Here, we show that the regulators of G protein signaling Rgs16 and Rgs8 are expressed in pancreatic progenitor and endocrine cells during development, then extinguished in adults, but reactivated in models of both type 1 and type 2 diabetes. Exendin-4, a glucagon-like peptide 1 (Glp-1)/incretin mimetic that stimulates beta-cell expansion, insulin secretion and normalization of blood glucose levels in diabetics, also promoted re-expression of Rgs16::GFP within a few days in pancreatic ductal-associated cells and islet beta-cells. These findings show that Rgs16::GFP and Rgs8::GFP are novel and early reporters of G protein-coupled receptor (GPCR)-stimulated beta-cell expansion after therapeutic treatment and in diabetes models. Rgs16 and Rgs8 are likely to control aspects of islet progenitor cell activation, differentiation and beta-cell expansion in embryos and metabolically stressed adults.


Subject(s)
Diabetes Mellitus, Type 1/embryology , Diabetes Mellitus, Type 1/pathology , Islets of Langerhans/embryology , Islets of Langerhans/pathology , RGS Proteins/metabolism , Aging/drug effects , Aging/pathology , Animals , Animals, Newborn , Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 1/genetics , Disease Models, Animal , Exenatide , Female , Gene Expression Regulation, Developmental/drug effects , Green Fluorescent Proteins/metabolism , Hyperglycemia/complications , Hyperglycemia/pathology , Insulin-Secreting Cells/drug effects , Insulin-Secreting Cells/metabolism , Insulin-Secreting Cells/pathology , Islets of Langerhans/drug effects , Islets of Langerhans/metabolism , Mice , Mice, Obese , Peptides/pharmacology , Pregnancy , RGS Proteins/genetics , Recombinant Fusion Proteins/metabolism , Regeneration/drug effects , Stem Cells/drug effects , Stem Cells/metabolism , Venoms/pharmacology
4.
BMJ ; 340: c623, 2010 Feb 24.
Article in English | MEDLINE | ID: mdl-20181638
5.
J Reprod Immunol ; 84(2): 117-23, 2010 Mar.
Article in English | MEDLINE | ID: mdl-20116109

ABSTRACT

Fetus-derived cells are present in the blood and tissues of the maternal body over a long period of time, even after delivery, resulting in fetal cell microchimerism. The exact process by which fetal cells cross the placental barrier to enter the maternal circulation is unclear. The objective of this paper was to determine the time during pregnancy that fetal cells with multilineage potential migrate to the maternal organs. Wild type female mice were crossbred with male transgenic mice, expressing enhanced green fluorescent protein (EGFP). Total hysterectomies were performed at different time points of pregnancy. On day 60 after surgery, mice were injected with either streptozotocin (STZ) to induce insulin-dependent diabetes mellitus, or vehicle. Detection and quantification of fetal cells were then undertaken in a variety of maternal organs via fluorescent microscopy and quantitative PCR amplification of the gfp transgene. In vehicle control mice, fetal cells were detected only in the maternal bone marrow. However on day 30 after STZ injection, fetal cells were detected not only in bone marrow but also in the maternal pancreas, liver and kidney. Histological analysis showed differentiated fetal cells within the pancreatic acinar cells, hepatocytes and tubular epithelial cells. Their morphological appearance was indistinguishable from their maternal counterparts, and their frequency in these organs was constant, regardless of the timing of hysterectomy. These results indicate that most fetal cells with multilineage potential in maternal tissues migrate to the maternal body early after implantation, and thereafter sustain their population over the long term after delivery.


Subject(s)
Chimerism/chemically induced , Diabetes Mellitus, Type 1/pathology , Fetus/pathology , Pancreas/pathology , Pluripotent Stem Cells/metabolism , Animals , Cell Differentiation/drug effects , Cell Movement/drug effects , Diabetes Mellitus, Type 1/chemically induced , Diabetes Mellitus, Type 1/embryology , Embryo Implantation , Female , Hysterectomy , Kidney/drug effects , Kidney/pathology , Liver/drug effects , Liver/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Pancreas/drug effects , Placental Circulation , Pluripotent Stem Cells/pathology , Pregnancy , Streptozocin/administration & dosage
6.
Diabetes Care ; 32(11): 2050-5, 2009 Nov.
Article in English | MEDLINE | ID: mdl-19690080

ABSTRACT

OBJECTIVE: Cardiomyopathy is noted in up to 40% of infants of diabetic mothers, and the exact mechanisms are unknown. The aim of this study was to determine whether fetal serum markers of cardiac function differ between normal and type 1 diabetic pregnancies and to examine the relationship between these markers and fetal cardiac structure and function. RESEARCH DESIGN AND METHODS: This was a prospective observational study of 45 type 1 diabetic pregnancies and 39 normal pregnancies. All participants had concentrations of fetal pro-B-type natriuretic peptide (proBNP) and troponin-T (TnT) measured at the time of delivery. All patients with type 1 diabetes had Doppler evaluation of the umbilical artery, middle cerebral artery, and ductus venosus in the third trimester, and a subset (n = 21) had detailed fetal echocardiograms performed in each trimester. RESULTS: Fetal proBNP and TnT concentrations were higher in the diabetic cohort than in the normal cohort (P < 0.05). ProBNP correlated positively with interventricular septum thickness (P < 0.05) but not with cardiac function indexes in the third trimester. In patients with poor glycemic control, there was a significant positive correlation (P < 0.05) between fetal TnT and the third trimester umbilical artery pulsatility index. There were also increased levels of fetal TnT in infants with poor perinatal outcome (P < 0.05). CONCLUSIONS: Biochemical markers of cardiac dysfunction are elevated in infants of diabetic mothers, especially those with cardiomyopathy or poor perinatal outcome. Hyperglycemia in early pregnancy may affect myocardial and placental development, thus contributing to the susceptibility to hypoxia seen in these infants.


Subject(s)
Diabetes Mellitus, Type 1/blood , Natriuretic Peptide, Brain/blood , Pregnancy in Diabetics/blood , Troponin T/blood , Adult , Age of Onset , Apgar Score , Birth Weight , Body Mass Index , Diabetes Mellitus, Type 1/embryology , Diabetic Angiopathies/blood , Female , Fetal Blood/chemistry , Fetal Macrosomia/epidemiology , Glycated Hemoglobin/metabolism , Humans , Infant, Newborn , Parity , Pregnancy , Pregnancy Complications/blood , Prospective Studies , Reference Values
7.
Diabetes Care ; 32(1): 94-9, 2009 Jan.
Article in English | MEDLINE | ID: mdl-18835948

ABSTRACT

OBJECTIVE: In a prospective birth cohort study, we followed infants who had a first-degree relative with type 1 diabetes to investigate the relationship between early growth and infant feeding and the risk of islet autoimmunity. RESEARCH DESIGN AND METHODS: Infants with a first-degree relative with type 1 diabetes were identified during their mother's pregnancy. Dietary intake was recorded prospectively to determine duration of breast-feeding and age at introduction of cow's milk protein, cereals, meat, fruit, and vegetables. At 6-month reviews, length (or height) and weight, antibodies to insulin, GAD65, the tyrosine phosphatase-like insulinoma antigen, and tissue transglutaminase were measured. Islet autoimmunity was defined as persistent elevation of one or more islet antibodies at consecutive 6-month intervals, including the most recent measure, and was the primary outcome measure. RESULTS: Follow-up of 548 subjects for 5.7 +/- 3.2 years identified 46 children with islet autoimmunity. Weight z score and BMI z score were continuous predictors of risk of islet autoimmunity (adjusted hazard ratios 1.43 [95% CI 1.10-1.84], P = 0.007, and 1.29 [1.01-1.67], P = 0.04, respectively). The risk of islet autoimmunity was greater in subjects with weight z score >0 than in those with weight z score < or =0 over time (2.61 [1.26-5.44], P = 0.01). Weight z score and BMI z score at 2 years and change in weight z score between birth and 2 years, but not dietary intake, also predicted risk of islet autoimmunity. CONCLUSIONS: Weight gain in early life predicts risk of islet autoimmunity in children with a first-degree relative with type 1 diabetes.


Subject(s)
Diabetes Mellitus, Type 1/genetics , Islets of Langerhans/immunology , Mothers , Nuclear Family , Autoantibodies/blood , Autoimmunity , Body Mass Index , Child , Child, Preschool , Diabetes Mellitus, Type 1/embryology , Diabetes Mellitus, Type 1/epidemiology , Diabetes Mellitus, Type 1/microbiology , Fathers , Female , HLA-A Antigens/immunology , HLA-B Antigens/immunology , HLA-DR Antigens/genetics , HLA-DR Antigens/immunology , Humans , Male , Predictive Value of Tests , Pregnancy , Risk Assessment , Siblings , T-Lymphocytes/immunology , Weight Gain
8.
Diabetes Metab Res Rev ; 24(6): 486-97, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18551708

ABSTRACT

BACKGROUND: The activation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in pancreatic beta-cells has been thought to play a central role in Ca2+-mediated insulin secretion. However, the physiological and pathological significance of CaMKII activation in pancreatic beta-cells has never been investigated in vivo. METHODS: We generated transgenic (TG) mice overexpressing the constitutively active-type CaMKIIalpha (Thr286Asp) in beta-cells. The mice were extensively examined histologically and biochemically. Time-course changes of blood glucose, haemoglobin A1C and insulin were also determined. RESULTS: Western blot and immunohistochemical analyses showed overexpression of CaMKIIalpha proteins in pancreatic beta-cells of TG mice. All TG mice developed severe hypoinsulinaemic diabetes by P28. In vivo BrdU labelling analysis revealed that cell proliferation in TG islets is severely impaired. Immunohistochemical examination revealed accumulations of NF-kappaB in nuclei of TG beta-cells at P21, which are associated with DNA laddering, a hallmark of apoptosis. At P28, pancreatic and serum insulin levels were both significantly (p < 0.05) lower in TG mice (0.037 +/- 0.005 ng/microg and 0.50 +/- 0.01 ng/mL) than in wild-type mice (0.997 +/- 0.093 ng/microg and 2.50 +/- 0.22 ng/mL). TG mice at P140 showed enlargement of kidney, mesangial expansion and glomerulosclerosis, which are associated with urinary albumin excretion. TG mice at P140-P168 developed severe retinal lesions such as disrupted ganglion cells and showed a flat pattern in electroretinography. CONCLUSIONS: The TG mice established herein will be valuable as a novel model of severe insulin-dependent diabetes accompanied by an early progression of diabetic micro-vascular complications.


Subject(s)
Calcium-Calmodulin-Dependent Protein Kinase Type 2/genetics , Diabetes Mellitus, Type 1/genetics , Diabetic Angiopathies/genetics , Diabetic Nephropathies/genetics , Insulin-Secreting Cells/enzymology , Amino Acid Substitution , Animals , Animals, Genetically Modified , Aspartic Acid , DNA Primers , Diabetes Mellitus, Type 1/embryology , Diabetic Angiopathies/enzymology , Diabetic Nephropathies/enzymology , Disease Models, Animal , Disease Progression , Female , Mice , Mice, Inbred Strains , Threonine
9.
Ontogenez ; 37(4): 279-85, 2006.
Article in Russian | MEDLINE | ID: mdl-17022442

ABSTRACT

Type 1 diabetes mellitus is a chronic disease characterized by autoimmune degradation of insulin-producing beta-cells. It was shown in a number of epidemiological studies of seasonality of birth in children with type 1 diabetes that the autoimmune process began during fetal and postnatal development. No such studies were carried out in the former Soviet Union countries. The aim of the present study is to compare the seasonal birth month pattern in patients with type 1 diabetes (10780 men and 9337 women) born in 1960-2002 to that in the total population of Ukraine (14 785601 men and 13 911370 women) born during the same period. Significant differences were found between these two populations: chi-squared = 103.97, p < 0.0001 and 135.17, p < 0.0001 in men and women, respectively. The results of cosinor analysis showed similar sinusoidal birth patterns of patients with type 1 diabetes in all sub-groups, irrespective of the age of clinical disease expression: 0-9, 10-19, or 20-29 years. In all cases, the highest and lowest predispositions to type 1 diabetes were inherent in the people born in spring and autumn, respectively. We propose that seasonal differences in the birth pattern in the two above populations could be due to long-term programming of glucose-insulin metabolism determined by the effect of certain seasonal factors during early ontogenesis.


Subject(s)
Diabetes Mellitus, Type 1/epidemiology , Seasons , Adolescent , Adult , Age of Onset , Child , Child Development , Child, Preschool , Diabetes Mellitus, Type 1/embryology , Diabetes Mellitus, Type 1/etiology , Embryonic Development , Female , Humans , Male , Ukraine/epidemiology
10.
Diabetologia ; 49(1): 20-4, 2006 Jan.
Article in English | MEDLINE | ID: mdl-16362279

ABSTRACT

Overload of the beta cell, mediated by a variety of mechanisms, may sensitise it to immune damage and apoptosis, and thus accelerate ongoing autoimmune processes leading to its destruction. Environmental risk determinants that may exert such overload effects include insulin resistance due to excess fat cell accumulation, and increased insulin requirement due to a high growth rate, physical stress (infection, inflammation) or psychological stress. The increasing incidence of childhood diabetes, and the shift to younger age at onset, is unlikely to be driven by environmental risk factors that have been associated with initiation of autoimmunity, e.g. virus infections or early infant feeding. Risk factors that may accelerate beta cell destruction have shown a steady increase in the population, and are more plausible causes of such a pattern of change. Child growth, weight and birthweight are well-established estimates of community wealth and increase in most countries of Europe. Overfeeding of children early in life leads to both accelerated growth and weight, and even a moderate excess of child growth, not necessarily associated with obesity, is associated with risk of type 1 diabetes. New, safe and effective immune-modulating drugs for possible arrest of the autoimmune process may become available in time, but in the interim these accelerating factors may be targeted. Public health programmes for pregnant mothers and young families, aiming at changing overfeeding and the sedentary lifestyle of the children would be preferable to other alternatives. Interventions such as these would be safe and could potentially influence future risks of type 1 and type 2 diabetes and other major threats to adult health.


Subject(s)
Diabetes Mellitus, Type 1/epidemiology , Age of Onset , Child , Diabetes Mellitus, Type 1/embryology , Humans , Incidence , Models, Biological , Prediabetic State/epidemiology
11.
Niger J Physiol Sci ; 21(1-2): 37-41, 2006.
Article in English | MEDLINE | ID: mdl-17242732

ABSTRACT

Intake of nitrosamine-rich food has been implicated in the pathogenesis of childhood type 1 diabetes mellitus. The present study therefore examines a possible relationship between consumption of charred meat, rich in nitrosamine in pregnancy and the corresponding development of type 1 diabetes in litters. Determination of blood glucose and serum insulin levels in litters showed percent charred meat related increase in the mean blood glucose values of 64.1 +/- 1.39 mg/dl compared with the mean control value of 53.8 +/- 3.78 mg/dl and a corresponding reduction in the mean serum insulin values of 2.0 +/- 0.43 microU/ml compared with 5.8 +/- 0.29 microU/ml in the control [P < 0.05]. There were no significant changes in the mean blood glucose level and serum insulin level among the corresponding pregnant rats, hence, no evidence of diabetes mellitus. These results suggest that meat, when subjected to charcoal fire roasting may be hazardous to the foetus and a causative factor in the development of type 1 diabetes mellitus in the litters.


Subject(s)
Diabetes Mellitus, Type 1/etiology , Hot Temperature , Meat/adverse effects , Animals , Animals, Newborn , Blood Glucose/analysis , Body Weight , Charcoal , Diabetes Mellitus, Type 1/blood , Diabetes Mellitus, Type 1/embryology , Female , Food Handling/methods , Insulin/blood , Meat/analysis , Mice , Mice, Inbred Strains , Nitrosamines/administration & dosage , Nitrosamines/toxicity , Pregnancy , Rats , Rats, Inbred Strains
12.
J Autoimmun ; 22(4): 287-96, 2004 Jun.
Article in English | MEDLINE | ID: mdl-15120752

ABSTRACT

Bafilomycin, a plecomacrolide produced by plant-pathogenic Streptomyces, contaminates tuberous vegetables and has adverse effects on beta cells in adult mice. We therefore determined whether dietary bafilomycin influenced the progression of diabetes in the non-obese diabetic (NOD) mouse model of autoimmune Type 1 diabetes. Parent NOD mice were fed sub-toxic doses of bafilomycin in drinking water from conception until weaning, or various times after birth and blood glucose was monitored in the offspring. Pancreatic islets in neonatal offspring were examined histologically by quantitative morphometry and islet cell apoptosis was estimated by TUNEL assay. Exposure in utero to bafilomycin but not after birth significantly accelerated onset and increased the frequency of diabetes. In exposed mice, pancreatic islet organogenesis was disrupted, characterized by a striking increase in beta-cell mass and a shift in timing of the normal wave of neonatal islet cell apoptosis from 2 weeks to 4 weeks of age. We postulate that accelerated onset and increased incidence of diabetes later in life result from disruption of the normal turnover of beta cells in the neonatal pancreas. Since bafilomycin and related plecomacrolides contaminate Streptomyces-infected vegetables, dietary exposure during pregnancy could be an important and previously unsuspected environmental component of human Type 1 diabetes.


Subject(s)
Diabetes Mellitus, Type 1/etiology , Islets of Langerhans/drug effects , Islets of Langerhans/embryology , Macrolides/toxicity , Age Factors , Animals , Animals, Newborn , Apoptosis/drug effects , Autoimmunity/drug effects , Diabetes Mellitus, Type 1/embryology , Diabetes Mellitus, Type 1/pathology , Female , Food Contamination , Food Microbiology , Humans , Islets of Langerhans/pathology , Macrolides/administration & dosage , Male , Maternal-Fetal Exchange , Mice , Mice, Inbred NOD , Pregnancy , Streptomyces/pathogenicity , Vegetables/microbiology
13.
Paediatr Perinat Epidemiol ; 18(1): 33-9, 2004 Jan.
Article in English | MEDLINE | ID: mdl-14738545

ABSTRACT

The aim of this study was to investigate whether prenatal and social factors are associated with the development of type 1 diabetes. A case-control study was conducted in Belgrade during the period 1994-97. A total of 105 children 41 weeks (11.11, [1.80, 68.52]); mother's consumption of foods containing nitrosamines during pregnancy (3.14, [1.68, 5.87]); and consumption of alcohol by father (4.54, [2.34, 8.79]).


Subject(s)
Diabetes Mellitus, Type 1/etiology , Prenatal Exposure Delayed Effects , Adolescent , Age Distribution , Case-Control Studies , Child , Child, Preschool , Diabetes Mellitus, Type 1/embryology , Family Characteristics , Female , Humans , Infant , Logistic Models , Male , Pregnancy , Risk Factors , Sex Distribution , Socioeconomic Factors
14.
Endocrinology ; 144(5): 1703-11, 2003 May.
Article in English | MEDLINE | ID: mdl-12697674

ABSTRACT

GLUT8 is a novel glucose transporter protein that is widely distributed in tissues including liver, a central organ of regulation of glucose homeostasis. The purpose of the current study was to investigate expression and regulation of hepatic GLUT8 mRNA and protein. Therefore, Northern and immunoblot analysis, semiquantitative RT-PCR, and immunofluorescence microscopy were performed using mouse livers at different stages of embryonic and postnatal development and in type 1 (streprozotocin treated) and type 2 (GLUT4 heterozygous) diabetes. GLUT8 mRNA and protein expression in embryonic liver was differentially regulated depending on the prenatal and postnatal developmental stage of the mice. Immunofluorescence microscopy of liver from wild-type mice demonstrated the highest levels of GLUT8 protein in perivenous hepatocytes pointing to its role in regulation of glycolytic flux. In diabetic scenarios, GLUT8 mRNA levels were correlated with circulating insulin; specifically, GLUT8 mRNA decreased in a type 1 diabetes model and increased in a type 2 diabetes model, suggesting a regulatory role for insulin in GLUT8 mRNA expression. While up-regulation of GLUT8 protein occurred in both models of diabetes, only in streptozotocin diabetic livers was GLUT8 zonation altered. These data demonstrate that GLUT8 mRNA and protein are differentially regulated in liver in response to physiologic and pathologic (diabetes) milieu and suggests that GLUT8 is intimately linked to glucose homeostasis.


Subject(s)
Diabetes Mellitus, Type 1/metabolism , Diabetes Mellitus, Type 2/metabolism , Liver/metabolism , Monosaccharide Transport Proteins/metabolism , Muscle Proteins , Animals , Animals, Newborn/metabolism , Diabetes Mellitus, Experimental/embryology , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Type 1/embryology , Diabetes Mellitus, Type 2/embryology , Diabetes Mellitus, Type 2/genetics , Female , Fetus/metabolism , Gene Deletion , Glucose Transport Proteins, Facilitative , Glucose Transporter Type 4 , Heterozygote , Immunologic Techniques , Mice , Mice, Inbred CBA , Monosaccharide Transport Proteins/genetics , RNA, Messenger/metabolism , Reference Values
15.
J Intern Med ; 253(3): 343-50, 2003 Mar.
Article in English | MEDLINE | ID: mdl-12603502

ABSTRACT

OBJECTIVES: Intrauterine growth retardation, as seen in individuals with low weight at birth, may give rise to a reduction in nephron number. Oligonephropathy has been linked to hypertension and renal disease in adult life. We tested the concept that low weight at birth acts as a risk factor for progression of diabetic nephropathy. DESIGN AND SUBJECTS: We performed an observational follow-up study of 161 (97 men) type 1 diabetic patients with diabetic nephropathy [mean age (SD): 35 (11) years, mean duration of diabetes: 22 (8) years]. All patients had been followed for at least 3 years [median (range): 8 (3-20)] with at least three measurements [9 (3-31)] of glomerular filtration rate (GFR) (51Cr-EDTA). Information about birth size was obtained from midwife registrations. SETTINGS: Steno Diabetes Center, a tertiary referral centre. MAIN OUTCOME MEASURES: Loss of kidney function according to birth weight and weight/length ratio at birth. RESULTS: There was no correlation in univariate analysis between birth weight or weight/length ratio and rate of decline in GFR, neither in men nor in women. Furthermore, the 27 patients with birth weights below the 20th centile had a rate of decline in GFR [median (range)] similar to the 134 patients above: 2.6 (-4.7; 9.6) vs. 3.4 (-2.3; 19.3) mL min(-1) year(-1), respectively (NS). A multiple regression analysis revealed that albuminuria, arterial blood pressure, and haemoglobin A1C during follow-up showed a significant correlation with the decline in GFR [R2 (adjusted) = 0.34], whereas birth weight and birth weight/length ratio did not. CONCLUSIONS: Our study does not suggest that weight at birth is associated with progression of established diabetic nephropathy in type 1 diabetic patients, whilst several other potential modifiable risk factors were identified.


Subject(s)
Diabetes Mellitus, Type 1/etiology , Diabetic Nephropathies/etiology , Infant, Low Birth Weight/physiology , Adult , Body Height , Diabetes Mellitus, Type 1/embryology , Diabetic Nephropathies/embryology , Disease Progression , Female , Fetal Growth Retardation/physiopathology , Follow-Up Studies , Glomerular Filtration Rate/physiology , Humans , Infant, Newborn , Kidney Function Tests , Male , Regression Analysis , Risk Factors
16.
J Intern Med ; 252(6): 524-8, 2002 Dec.
Article in English | MEDLINE | ID: mdl-12472913

ABSTRACT

OBJECTIVES: To investigate if low birth weight as a consequence of intrauterine malnutrition is a risk factor for the later development of diabetic nephropathy. DESIGN AND SUBJECTS: In a case-control set-up a group of type 1 diabetic subjects with diabetic nephropathy (n = 51) and a matched control group with normal kidney function (n = 51) were compared. Diabetic nephropathy and normal kidney function were defined as urinary albumin excretion rate above 200 microg min-1 and below 20 microg min-1, respectively. The birth weights were all obtained from the midwives' original records. SETTING: The patients were identified from a population-based study of chronic diabetic complications in the Funen County, Denmark. MAIN OUTCOMES: Birth weights according to the presence of diabetic nephropathy. RESULTS: The median (10-90 percentile) birth weights were 3,600 g (2,960-4,274) in the group with diabetic nephropathy and 3,600 g (2,880-4,220) in the group without nephropathy, P = 0.52. In the lower quartile of birth weights the median (10-90 percentile) birth weights were 3,000 g (2,780-3,200) in the group with nephropathy versus 2,850 g (2,250-3,175) in the group without nephropathy, P = 0.07. In the upper quartile the median (10-90 percentile) birth weights were 4,225 g (4,000-4,741) in the nephropathy group and 4,000 g in the group without nephropathy, P = 0.13. We found no significant correlation between birth weights and log urinary albumin excretion rate (r = 0.148, P = 0.14) and no difference in the number of patients with nephropathy in the lower versus upper quartiles of birth weights. CONCLUSION: We found no evidence of low birth weight as a risk factor for the development of diabetic nephropathy.


Subject(s)
Diabetes Mellitus, Type 1/embryology , Diabetic Nephropathies/embryology , Fetal Diseases , Infant, Low Birth Weight , Nutrition Disorders/embryology , Adolescent , Adult , Case-Control Studies , Female , Humans , Infant, Newborn , Male , Middle Aged , Risk Factors
17.
Obstet Gynecol ; 95(2): 190-4, 2000 Feb.
Article in English | MEDLINE | ID: mdl-10674578

ABSTRACT

OBJECTIVE: To determine the time of growth acceleration in fetuses of insulin-dependent diabetic women who are large for gestational age (LGA) at birth and the relationship between growth acceleration and diabetic control throughout pregnancy. METHODS: We studied a consecutive sample of 76 women with insulin-dependent diabetes divided by those who delivered LGA or normally grown infants. Fetal abdominal circumference (AC) was measured ultrasonically at regular intervals between 20 and 34 weeks' gestation. Diabetic control was assessed by regular measurement of glycosylated hemoglobin and capillary blood glucose levels. RESULTS: A significant difference in fetal AC between groups developed between 20 and 24 weeks' gestation, and the LGA group continued to have accelerated fetal growth. Between 18 and 24 weeks glycosylated hemoglobin and capillary blood glucose concentrations were significantly higher in women who delivered LGA infants. After 28 weeks, blood glucose concentrations and glycosylated hemoglobin did not differ significantly between groups. There was a nonsignificant trend toward more vaginal deliveries in the normal group (45% versus 32%). CONCLUSION: In insulin-dependent diabetic pregnancy, although actual growth acceleration occurred from about 20 weeks' gestation, growth potential of fetuses appeared to be determined by prevailing maternal glucose concentrations before then. Excessive growth continued despite subsequent satisfactory glucose control. If strict blood glucose control is maintained during first and second trimesters, it might reduce the incidence of LGA infants.


Subject(s)
Diabetes Mellitus, Type 1/blood , Embryonic and Fetal Development , Fetal Macrosomia/blood , Pregnancy in Diabetics/blood , Abdomen/diagnostic imaging , Abdomen/embryology , Adult , Blood Glucose/analysis , Diabetes Mellitus, Type 1/embryology , Diabetes Mellitus, Type 1/prevention & control , Female , Fetal Macrosomia/diagnostic imaging , Fetal Macrosomia/embryology , Glycated Hemoglobin/analysis , Humans , Pregnancy , Pregnancy Outcome , Pregnancy in Diabetics/embryology , Pregnancy in Diabetics/prevention & control , Ultrasonography, Prenatal
18.
Obstet Gynecol ; 95(2): 195-8, 2000 Feb.
Article in English | MEDLINE | ID: mdl-10674579

ABSTRACT

OBJECTIVE: To measure insulin and glucagon concentrations in amniotic fluid (AF) collected near term in basal conditions and after an arginine test in diabetic, rhesus-isoimmunized, and control pregnant women. METHODS: At baseline, AF was collected from 44 diabetic, 32 rhesus-isoimmunized, and 27 control pregnant women in late pregnancy. Fifty-two diabetic, six rhesus-isoimmunized, and nine control pregnant women had amniocentesis 2 hours after arginine infusion (30 g intravenous/30 minutes) at 33-36 weeks. RESULTS: Baseline AF glucose concentrations were significantly greater in diabetic women than the other conditions, and they related to the gestational age in the women with hemolytic disease of the newborn. Insulin and glucagon AF content of isoimmunized pregnancies overlapped controls, whereas insulin and insulin/glucagon molar ratios were significantly higher, and glucagon values lower, in diabetic pregnancies compared with isoimmunized and control pregnancies. In isoimmunized pregnancies, the AF concentrations of glucose, insulin, and glucagon were correlated with gestational age (less than 34, 34 weeks or more). The samples collected after arginine infusion, compared with those collected at baseline, showed significantly greater insulin and insulin/glucagon molar ratio values in diabetic (28 +/- 5 versus 11 +/- 1 microU/mL, P = .001; 29.4 +/- 1.7 versus 12.0 +/- 2.8, P = .001) and in Rh pregnant women (18 +/- 6 versus 7.7 +/- 0.7 microU/mL, P = .001; 30 +/- 9 versus 3.4 +/- 0.4 I/G, P = .001), whereas no significant difference was observed in the controls. CONCLUSION: Basal islet hormone concentrations in AF are modified by maternal diabetes and further influenced by arginine administration. Arginine produces an AF response that is similar in pregnancies complicated by diabetes mellitus and rhesus-isoimmunization, despite different (hyperglycemia and euglycemia) maternal blood glucose levels.


Subject(s)
Diabetes Mellitus, Type 1/embryology , Pancreas/embryology , Pancreas/physiology , Pregnancy in Diabetics/embryology , Rh Isoimmunization/embryology , Adult , Amniotic Fluid/metabolism , Arginine/administration & dosage , Diabetes Mellitus, Type 1/physiopathology , Female , Glucagon/metabolism , Glucose/metabolism , Humans , Infusions, Intravenous , Insulin/metabolism , Pregnancy , Pregnancy in Diabetics/physiopathology , Rh Isoimmunization/physiopathology
19.
Br J Obstet Gynaecol ; 105(6): 661-6, 1998 Jun.
Article in English | MEDLINE | ID: mdl-9647158

ABSTRACT

OBJECTIVE: To determine the reproducibility of duplex Doppler waveform analysis and fetal cardiac interventricular septal thickness measurement and to compare these parameters in matched pregnancies with and without well-controlled maternal Type 1 diabetes at 18-20 weeks of gestation. DESIGN: A prospective blind twin cohort study and a blinded inter-observer and intra-observer agreement study. SETTING: A tertiary referral prenatal diagnostic unit within a university hospital. RESULTS: Good inter- and intra-observer agreement was found for the measurement of transvalvular peak flow velocities and the duration of ventricular ejection in the fetal heart. Inter-observer agreement for aortic flow acceleration rate was poor. M-mode measurement of interventricular septal thickness showed moderate reproducibility. The mean (SD) width of the interventricular septum in the fetuses of well controlled diabetic women was 2 1 mm (0.2 mm), and was significantly greater (P=0.01) when compared with the corresponding value in matched controls [1.9 mm (0.2 mm)]. No cardiac functional differences were evident. CONCLUSIONS: On-screen video analysis of Doppler cardiac flow waveforms and M-mode measurement of intraventricular septal thickness demonstrated good reproducibility. The fetuses of well controlled diabetic pregnancies demonstrated signs of altered cardiac morphology early in pregnancy, before any evident alterations in cardiac function.


Subject(s)
Diabetes Mellitus, Type 1/physiopathology , Heart Septum/embryology , Pregnancy in Diabetics , Blood Flow Velocity , Cohort Studies , Diabetes Mellitus, Type 1/embryology , Diabetes Mellitus, Type 1/pathology , Double-Blind Method , Female , Gestational Age , Heart Septum/pathology , Heart Septum/physiopathology , Humans , Observer Variation , Pregnancy , Pregnancy in Diabetics/embryology , Pregnancy in Diabetics/pathology , Pregnancy in Diabetics/physiopathology , Prospective Studies , Reproducibility of Results , Ultrasonography, Doppler , Ultrasonography, Prenatal
20.
Arkh Patol ; 60(6): 33-6, 1998.
Article in Russian | MEDLINE | ID: mdl-9949903

ABSTRACT

Fetal kidneys from mothers with late gestosis, diabetes mellitus-1 and chronic glomerulonephritis were studied. There were features of the maturation slowing down and some disturbances in differentiation of rental tissue were revealed. Local degenerative, membranous, proliferative and fibroplastic changes with formation of immune complexes including IgM and C3-complement in late gestosis, IgA, G, C3-complement fractions IgG, M, C3-complement fraction and traces of membranous and proliferative alteration were observed in chronic glomerulonephritis, they were less frequent in diabetes mellitus in mothers, and not so often in late gestosis. Activation of collagen production of types I, III, IV and V was most commonly observed in diabetes mellitus, in chronic glomerulonephritis and late gestosis, it being more rare.


Subject(s)
Diabetes Mellitus, Type 1/embryology , Glomerulonephritis/embryology , Kidney/pathology , Pre-Eclampsia/embryology , Pregnancy in Diabetics/embryology , Antigen-Antibody Complex/metabolism , Chronic Disease , Collagen/metabolism , Complement C3/metabolism , Female , Gestational Age , Humans , Immunoglobulins/metabolism , Kidney/embryology , Kidney/immunology , Kidney/metabolism , Periodic Acid-Schiff Reaction , Pregnancy
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