Intergenerational effects of birth weight on glucose tolerance and reproductive performance

Women who were themselves small-for-gestational age (SGA) are at a greater risk of adulthood diseases such as non-insulin-dependent diabetes mellitus (NIDDM), and twice at risk of having an SGA baby themselves. The aim of this study was to examine the intergenerational pig. Low (L) and normal (N) birth weight female piglets were followed throughout their first pregnancy (generation 1 (0)). After they had given birth, the growth and development of the lightest (I) and heaviest (n) female piglet from each litter were monitored until approximately 5 months of age (generation 2 (G2)). A glucose tolerance test (GTT) was conducted on G1 pig at similar to 6 months of age and again during late pregnancy; a GTT was also conducted on G2 pigs at similar to 4 months of age. G1 L offspring exhibited impaired glucose metabolism in later life compared to their G1 N sibling but in the next generation a similar scenario was only observed between I and n offspring born to G1 L mothers. Despite G1 L mothers showing greater glucose intolerance in late pregnancy and a decreased litter size, average piglet birth weight was reduced and there was also a large variation in litter weight; this suggests that they were, to some extent, prioritising their nutrient intake towards themselves rather than promoting their reproductive performance. There were numerous relationships between body shape at birth and glucose curve characteristics in later life, which can, to some extent, be used to predict neonatal outcome. In conclusion, intergenerational effects are partly seen in the pig. It is likely that some of the intergenerational influences may be masked due to the pig being a litter-bearing species.

Role of leptin receptors in the development of obesity

The focus of this dissertation was leptin and the leptin receptor, and the role of these genes (OB and OB-R) in the development of obesity and type 2 diabetes in humans and Psammomys obesus, a polygenic rodent model of obesity and type 2 diabetes. Studies in humans showed that circulating leptin concentrations were positively associated with adiposity, and independently associated with circulating insulin and triglyceride concentrations. Analysis of two leptin receptor sequence polymorphisms in a Caucasian Australian population and a population of Nauruan males, with very high prevalence rates of obesity, showed no associations between sequence variation within the OB-R gene and obesity- or diabetes-related phenotypic measures. In addition, these two OB-R polymorphisms were not associated with longitudinal changes in body mass or composition in either of the populations examined. A unique analysis of the effects of multiple gene defects in the Nauruan population, demonstrated that the presence of sequence alterations in both the OB and OB-R genes were associated with insulin resistance. Psammomys obesus is regarded as an excellent rodent model in which to study the development of obesity and type 2 diabetes in humans. Examination of circulating leptin concentrations in Psammomys revealed that, as in humans, leptin concentrations were associated with adiposity, and independently associated with circulating insulin concentrations. This animal model was utilised to examine expression of OB-R, and the regulation of expression of this gene after dietary manipulation. OB-R is known to have several isoforms, and in particular, OB-RA and OB-RB gene expression were examined. OB-RB is the main signalling isoform of the leptin receptors. It has a long intracellular domain and has previously been shown to play an important role in energy balance and body weight regulation in rodents and humans. OB-RA is a much shorter isoform of OB-R, and although it lacks the long intracellular domain necessary to activate the JAK/STAT pathway, OB-RA is also capable of signalling, although to a lesser degree than OB-RB. OB-RA is found to be expressed almost ubiquitously throughout the body, and this isoform may be involved in transport of leptin into the cell, although its role remains unclear. OB-RA and OB-RB were both found to be expressed in a large number of tissues in Psammomys obesus. Interestingly, obese Psammomys were found to have lower levels of expression of OB-RA and OB-RB in the hypothalamus, compared to lean animals. This finding raises the possibility that decreased leptin signalling in the brain of obese, hyperleptinemic Psammomys obesus may contribute to the leptin resistance previously described in this animal model. However, the primary defect is unclear, as alternatively, increased circulating leptin concentrations may lead to down-regulation of leptin receptors. The effect of fasting on leptin concentrations and gene expression of OB-RA and OB-RB was also examined. A 24-hour fast resulted in no change in body weight, but a reduction in circulating leptin concentrations, and an increase in hypothalamic OB-RB gene expression in lean Psammomys. In obese animals, fasting again did not alter body weight, but resulted in an increase in both circulating leptin concentrations and hypothalamic OB-RB gene expression. In the liver, fasting resulted in a large increase in OB-RA gene expression in both lean and obese animals. These results highlighted the fact that regulation of leptin receptor gene expression in polygenic models of obesity and type 2 diabetes is complex, and not solely under the control of circulating leptin concentrations. Sucrose-feeding is an established method of inducing obesity and type 2 diabetes in rodents, and this experimental paradigm was utilised to examine the effects of longer term perturbations of energy balance on the leptin signalling pathway in Psammomys obesus. Addition of a 5% sucrose solution to the diet of lean and obese Psammomys resulted in increased body weight in both groups of animals, however only obese Psammomys showed increased fat mass and the development of type 2 diabetes. The changes in body mass and composition with sucrose-feeding were accompanied by decreased circulating leptin concentrations in both groups of animals, as well as a range of changes in leptin receptor gene expression. Sucrose-feeding increased hypothalamic OB-RB gene expression in obese Psammomys only, while in the liver there was evidence of a reduction in OB-RA and OB-RB gene expression in both lean and obese animals. The direct effects of sucrose on the leptin signalling pathway are unclear, however it is possible to speculate that the effect of sucrose to decrease leptin concentrations may have been involved in the exacerbation of obesity and the development of type 2 diabetes in obese Psammomys, From these studies, it appears that sequence variation in the OB and OB-R genes is unlikely to be a major factor in the etiology of obesity in human populations. The ability to examine regulation of expression of these genes in Psammomys obesus, however, has demonstrated that the effects of nutritional modifications on leptin receptor gene expression need closer attention. The role of the OB and OB-R genes in metabolism and the development of type 2 diabetes also warrants further examination, with particular attention on the differential effects of dietary modifications on leptin receptor gene expression across a range of tissues.

Metabolically important secreted proteins in Psammomys obesus

A new adipokine, chemerin, was identified and its expression in P. obesus and in humans suggests that it is an important contributor to the development of obesity and type 2 diabetes. Polymorphisms within the CHEMERIN gene further support its involvement in obesity and type 2 diabetes.

Body build : its influence on anthropometric measurements, fat distribution, body composition and carbohydrate metabolism

Examines the interrelationships between body build and body composition and carbohydrate and lipid metabolism in healthy young men and women. Results indicate that in women a low relative sitting height may be an early marker of susceptibility to abdominal obesity and its consequences, non insulin dependent diabetes and coronary heart disease.

Central regulation of energy balance in Psammomys obesus

This body of work focussed on the central regulation of energy balance in a polygenic animal model of obesity and type II diabetes, the Israeli Sand Rat. These studies investigated the role of a number of hypothalamic neuropeptides in the development of obesity, and highlighted the complex nature of this disease.

Exercise test and glucose homeostasis in rats treated with alloxan during the neonatal period or fed a high calorie diet

Background: Animal models appear well-suited for studies into the role of exercise in the prevention of non-insulin-dependent diabetes mellitus (NIDDM). The aim of the present study was to analyze glucose homeostasis and blood lactate during an exercise swimming test in rats treated with alloxan during the neonatal period and/or fed a high calorie diet from weaning onwards.Methods: Rats were injected with alloxan (200 mg/kg, i.p.) or vehicle (citrate buffer) at 6 days of age. After weaning, rats were divided into four groups and fed either a balanced diet or a high-caloric diet as follows: C, control group (vehicle + normal diet); A, alloxan-treated rats fed the normal diet; H, vehicle-treated rats fed the high-caloric diet; and HA, alloxan-treated rats fed the high-caloric diet.Results: Fasting serum glucose levels were higher in groups A and AH compared with the control group. The Homeostatic Model Assessment index varied in the groups as follows: H > A > HA = C. There were no differences in free fatty acids or blood lactate concentrations during the swim test.Conclusions: Alloxan-treated rats fed a normal or high-caloric diet have the potential to be used in studies analyzing the role physical exercise plays in the prevention of NIDDM.

COMPARACAO ENTRE MEDICAMENTOS ORAIS ATRAVES DAS TAXAS SERICAS DE GLICOSE, AMILASE, ACIDOS GRAXOS LIVRES E LIPOPROTEINAS DE ALTA DENSIDADE (HDL-COLESTEROL) NOS DIABETICOS DE AMBOS OS SEXOS, DA REGIAO DE ARARAQUARA, NAO-DEPENDENTES DE INSULINA

A study was carried out, on both sexes, to determine the effects of chlorpropamide (DIABINESE) and glibenclamide (DAONIL) on patients with Type II diabetes using as metabolic parameters the following serum: glucose, amilase, high density lipoprotein cholesterol, free fatty acids. The results indicated that both drugs were potentially similar in relation to glycemia, high density lipoprotein cholesterol, and free fatty acids, in both sexes. Chlorpropamide was significantly more effective in reducing amilase activity in male diabetics than glibenclamide. The above mentioned hypoglycemiants did not reduce glycemia to basic levels in either masculine or feminine groups of diabetics.

Daytime variations in glucose tolerance in people with impaired glucose tolerance

To determine whether glucose tolerance varies throughout the day in people with impaired glucose tolerance (IGT). We studied 15 healthy IGT, and 18 matched normal glucose tolerant (NGT) individuals. Blood samples were taken every 30-120 min during a 24 h period in which all individuals had three mixed meals and nocturnal sleep. We measured glucose, free fatty acids, specific insulin, intact proinsulin, cortisol and growth hormone. Variable responses were considered as concentrations and areas under the curves. Comparison between the groups was by Student's t-test, Mann-Whitney, and analysis of variance. Higher total glucose response, inappropriate normal total insulin response, and unproportionally increased proinsulin total response were observed in the IGT group. Lower glucose tolerance occurred in IGT after dinner, as in the NGT, and after breakfast associated with increased insulin response after breakfast, and similar proinsulin response after all three meals. IGT had higher glucose response than NGT after breakfast and lunch, similar insulin responses, and increased proinsulin-insulin ratio after all three meals. Data from this study demonstrate that IGT individuals present lower glucose tolerance in the evening, as those with NGT, and in the morning, as reported in patients with type 2 diabetes. © 2006 Elsevier B.V. All rights reserved.

Exercise training in the aerobic/anaerobic metabolic transition prevents glucose intolerance in alloxan-treated rats

Background: Ninety percent of cases of diabetes are of the slowly evolving non-insulin-dependent type, or Type 2 diabetes. Lack of exercise is regarded as one of the main causes of this disorder. In this study we analyzed the effects of physical exercise on glucose homeostasis in adult rats with type 2 diabetes induced by a neonatal injection of alloxan. Methods: Female Wistar rats aged 6 days were injected with either 250 mg/ kg of body weight of alloxan or citrate buffer 0.01 M (controls). After weaning, half of the animals in each group were subjected to physical training adjusted to meet the aerobic-anaerobic metabolic transition by swimming 1 h/day for 5 days a week with weight overloads. The necessary overload used was set and periodically readjusted for each rat through effort tests based on the maximal lactate steady state procedure. When aged 28, 60, 90, and 120 days, the rats underwent glucose tolerance tests (GTT) and their peripheral insulin sensitivity was evaluated using the HOMA index. Results: The area under the serum glucose curve obtained through GTT was always higher in alloxan-treated animals than in controls. A decrease in this area was observed in trained alloxan-treated rats at 90 and 120 days old compared with non-trained animals. At 90 days old the trained controls showed lower HOMA indices than the non-trained controls. Conclusion: Neonatal administration of alloxan induced a persistent glucose intolerance in all injected rats, which was successfully counteracted by physical training in the aerobic/anaerobic metabolic transition. © 2008 Mota et al; licensee BioMed Central Ltd.

Effects of 12-week overground walking training at ventilatory threshold velocity in type 2 diabetic women

This study analyzed the effects of overground walking training at ventilatory threshold (VT) velocity on glycaemic control, body composition, physical fitness and lipid profile in DM2 women. Nineteen sedentary patients were randomly assigned to a control group (CG; n=10, 55.9±2.2 years) or a trained group (TG; n=9, 53.4±2.3 years). Both groups were subjected to anthropometric measures, a 12-h fasting blood sampling and a graded treadmill exercise test at baseline and after a 12-week period, during which TG followed a training program involving overground walking at VT velocity for 20-60min/session three times/week. Significant group×time interactions (P<0.05) in glycated hemoglobin (HbA1c), body mass, body mass index (BMI), peak oxygen uptake (VO 2peak) and exercise duration were observed as effects of training exercise, whereas intervention did not induced significant changes (P>0.05) in fasting blood glucose, submaximal fitness parameters and lipid profile. Our results suggest that overground walking training at VT velocity improves long term glycaemic control, body composition and exercise capacity, attesting for the relevance of this parameter as an effective strategy for the exercise intensity prescription in DM2 population. © 2011 Elsevier B.V.

Determinants of blood pressure in type 2 diabetic subjects with high occurrence of inadequate glycemic control

Study design: Association study Objective: To analyze the association between different biological/behavioral risk factors and blood pressure in a sample of type 2 diabetes mellitus patients with poor glycemic control. Methods: A sample of 121 type 2 diabetic patients was selected in the Public Healthcare System in a middle size Brazilian city. Blood pressure was measured using an aneroid device, previously calibrated. Six determinants of blood pressure were taken into count: age, hypoglycemic agents, general obesity, abdominal obesity, eating behaviors and physical activity level. Results: The type 2 diabetic patients presented mean age of 60.1±8.9 years-old and, at least, one risk factor. Eating behaviors (OR adj= 0.31 [0.12-0.75]) and sports practice (OR adj= 0.12 [0.02-0.75]) constituted protective factors associated with lower systolic blood pressure. On the other hand, age was positively associated with high systolic blood pressure (OR adj= 3.81 [1.39-10.38]). Patients with 5-6 risk factors, presented higher values of systolic and (F= 3.857; p= 0.011 [post hoc with p= 0.039]), diastolic blood pressure (F= 4.158; p= 0.008 [post hoc with p= 0.036]) and increased occurrence of hypertension (p= 0.010). Conclusion: Our findings indicate that, behavioral variables were important determinants of blood pressure in type 2 diabetic patients with poor glycemic control and clustering of behavioral and biological risk factors increase the hypertension occurrence.

Muscle strength and ankle mobility for the gait parameters in diabetic neuropathies

Aims: To evaluate the spatio-temporal variables of gait and the isometric muscle strength component of the ankle in patients with peripheral diabetic neuropathy. Also, verify the relationship between these variables and gait parameters. Methods: This study involved 25 diabetic peripheral neuropathy (DPN) participants (62.4 ± 8.36 years) and 27 age-matched healthy control individuals (64.48 ± 6.21 years). The assessment of the spatio-temporal parameters of gait was performed using an electronic baropodometry treadmill. Prior to the collection data, each participant was instructed to walk on the treadmill in her/his habitual self-selected speed. Results: Diabetic neuropathy group showed impairment of gait, with a smaller stride and length speed of the cycle, and increased duration of support time. Restricted dorsiflexion mobility and increased plantarflexion mobility were found, with a decrease in muscle strength of the dorsiflexors and plantiflexors. There was a significant relationship between plantiflexor muscle strength and the length and speed of the gait cycle. Also the muscle strengths of the plantiflexors and dorsiflexors, and the range of motion of dorsiflexion were predictors of gait performance. Conclusions: The ankle, muscle strength and ankle mobility variables could explain changes in gait speed and range of motion in patients with DPN, allowing for the application of preventive strategies. © 2012 Elsevier Ltd.

Tissue factor gene expression in the adipose tissues of obese mice

Altered expression of proteins of the fibrinolytic and coagulation cascades in obesity may contribute to the cardiovascular risk associated with this condition. We previously reported that plasminogen activator inhibitor 1 (PAI-1) is dramatically up-regulated in the plasma and adipose tissues of genetically obese mice. This change may disturb normal hemostatic balance and create a severe hypofibrinolytic state. Here we show that tissue factor (TF) gene expression also is significantly elevated in the epididymal and subcutaneous fat pads from ob/ob mice compared with their lean counterparts, and that its level of expression in obese mice increases with age and the degree of obesity. Cell fractionation and in situ hybridization analysis of adipose tissues indicate that TF mRNA is increased in adipocytes and in unidentified stromal vascular cells. Transforming growth factor β (TGF-β) is known to be elevated in the adipose tissue of obese mice, and administration of TGF-β increased TF mRNA expression in adipocytes in vivo and in vitro. These observations raise the possibility that TF and TGF-β may contribute to the increased cardiovascular disease that accompanies obesity and related non-insulin-dependent diabetes mellitus, and that the adipocyte plays a key role in this process. The recent demonstration that TF also influences angiogenesis, cell adhesion, and signaling suggests that its exact role in adipose tissue physiology/pathology, may be complex.

Islet amyloid formation associated with hyperglycemia in transgenic mice with pancreatic beta cell expression of human islet amyloid polypeptide.

Pancreatic islet amyloid deposits are a characteristic pathologic feature of non-insulin-dependent diabetes mellitus and contain islet amyloid polypeptide (IAPP; amylin). We used transgenic mice that express human IAPP in pancreatic beta cells to explore the potential role of islet amyloid in the pathogenesis of non-insulin-dependent diabetes mellitus. Extensive amyloid deposits were observed in the pancreatic islets of approximately 80% of male transgenic mice > 13 months of age. Islet amyloid deposits were rarely observed in female transgenic mice (11%) and were never seen in nontransgenic animals. Ultrastructural analysis revealed that these deposits were composed of human IAPP-immunoreactive fibrils that accumulated between beta cells and islet capillaries. Strikingly, approximately half of the mice with islet amyloid deposits were hyperglycemic (plasma glucose > 11 mM). In younger (6- to 9-month-old) male transgenic mice, islet amyloid deposits were less commonly observed but were always associated with severe hyperglycemia (plasma glucose > 22 mM). These data indicate that expression of human IAPP in beta cells predisposes male mice to the development of islet amyloid and hyperglycemia. The frequent concordance of islet amyloid with hyperglycemia in these mice suggests an interdependence of these two conditions and supports the hypothesis that islet amyloid may play a role in the development of hyperglycemia.

High fat diet-induced hyperglycemia: prevention by low level expression of a glucose transporter (GLUT4) minigene in transgenic mice.

High-fat intake leading to obesity contributes to the development of non-insulin-dependent diabetes mellitus (NIDDM, type 2). Similarly, mice fed a high-fat (safflower oil) diet develop defective glycemic control, hyperglycemia, and obesity. To assess the effect of a modest increase in the expression of GLUT4 (the insulin-responsive glucose transporter) on impaired glycemic control caused by fat feeding, transgenic mice harboring a GLUT4 minigene were fed a high-fat diet. Low-level tissue-specific (heart, skeletal muscle, and adipose tissue) expression of the GLUT4 minigene in transgenic mice prevented the impairment of glycemic control and accompanying hyperglycemia, but not obesity, caused by fat feeding. Thus, a small increase (< or = 2-fold) in the tissue level of GLUT4 prevents a primary symptom of the diabetic state in a mouse model, suggesting a possible target for intervention in the treatment of NIDDM.