Subject(s)
Diabetes Mellitus, Type 2/etiology , Obesity/complications , Child Development/physiology , Diabetes Mellitus, Type 2/history , Diabetes Mellitus, Type 2/metabolism , Fetal Development/physiology , History, 20th Century , Humans , Infant , Insulin/metabolism , Insulin Resistance/physiology , Obesity/metabolism , PhenotypeABSTRACT
This study investigates the effects of diet-induced changes in maternal body condition on glucose tolerance in sheep. Welsh Mountain ewes were established, by dietary manipulation, at a body condition score of 2 (lower body condition [LBCS], n = 17) or >3 (higher body condition [HBCS], n = 19) prior to and during pregnancy. Birth weight and postnatal growth were similar in LBCS and HBCS offspring. In young adulthood, LBCS offspring had increased fasting glucose levels (3.8 +/- 0.07 vs 3.6 +/- 0.05 mM, P < .05), poorer glucose tolerance (2274 +/- 22.6 vs 2161 +/- 33 min/mM, P < .01), and reduced insulin secretion (0.58 +/- 0.05 vs 0.71 +/- 0.07 nM/min, P = .07). Increased fasting glycemia, mild glucose intolerance, and impaired initial insulin secretory response, as observed in LBCS offspring, are indictors of increased diabetes risk in humans. These findings suggest that altered maternal body composition and an imbalance between the fetal and postnatal environment influence offspring glucose tolerance.
Subject(s)
Glucose/metabolism , Nutritional Status/physiology , Sheep/physiology , Animal Nutritional Physiological Phenomena , Animals , Animals, Newborn , Birth Weight/physiology , Blood Glucose/metabolism , Body Constitution/physiology , Female , Glucose Tolerance Test , Insulin/blood , Male , Muscle, Skeletal/metabolism , Pregnancy , Random Allocation , Sheep/blood , Sheep/embryology , Sheep/metabolismABSTRACT
BACKGROUND: We aimed to investigate whether the insulin precursors, intact (IP) and 32-33 split proinsulin (SP), which are elevated in states of insulin resistance and predict type 2 diabetes, would be elevated in human immunodeficiency virus (HIV)-infected patients with lipodystrophy (LIPO). MATERIALS AND METHODS: Forty-three normoglycaemic HIV-infected patients [18 LIPO and 18 without lipodystrophy (NONLIPO) receiving antiretroviral drugs, and seven patients naïve to antiretroviral drugs (NAIVE)] were examined. Insulin precursors were measured during fasting, during an intravenous glucose tolerance test and during a hyperinsulinaemic-euglycaemic clamp, respectively. Insulin secretion rates (ISR) were determined by deconvolution of C-peptide concentrations. Disposition index (DI) was calculated as insulin sensitivity (Si(RD)) multiplied by the first-phase insulin response to intravenous glucose. RESULTS: LIPO exhibited increased fasting IP and SP (P < 0.05), a higher proportion of elevated fasting IP (3.1 pmol L(-1), 66% vs. 33% and 28%, P < 0.05) and SP (7.2 pmol L(-1), 50%, 11% and 0%, P < 0.01), reduced Si(RD) (> 50%, P < 0.001) and increased ISR (P < 0.001) compared with NONLIPO and NAIVE. Fasting SP and IP correlated positively with ISR (P < 0.001) and inversely and hyperbolically with Si(RD) (P < 0.001). Fasting SP/insulin ratio correlated inversely with Si(RD) (P < 0.05). Incremental IP + SP/insulin ratio after an intravenous glucose bolus correlated inversely with DI (P < 0.01), but did not differ between study groups. CONCLUSIONS: Proinsulin appeared to be increased in HIV-lipodystrophy, but no more than caused by the increased ISR. Nevertheless, the inverse correlations between SP/insulin ratio versus Si(RD) and incremental total proinsulin/insulin ratio versus DI may argue for a subtle beta-cell dysfunction in those patients with insulin resistance and low DI.
Subject(s)
Blood Glucose/metabolism , HIV-1 , HIV-Associated Lipodystrophy Syndrome/blood , Proinsulin/blood , Adult , Antiretroviral Therapy, Highly Active , Body Composition , C-Peptide/blood , Fasting/blood , Glucose Tolerance Test , HIV Infections/blood , HIV Infections/drug therapy , HIV Infections/physiopathology , HIV-Associated Lipodystrophy Syndrome/physiopathology , Humans , Hyperlipidemias/blood , Insulin/blood , Insulin Resistance , Male , Middle AgedABSTRACT
AIMS/HYPOTHESIS: We examined whether associations between low birthweight and adult chronic cardio-metabolic disease were dependent upon birthweight alone, or on interactions with BMI, fat accumulation either generally or abdominally, or attained height in young South African adults. METHODS: Blood pressure (BP), lipids, glucose tolerance, insulin sensitivity and secretion (homeostasis model) were measured in 20-year-olds (n = 132) born at full term and with birthweights on or below the tenth centile (underweight for gestational age [UFA]) or between the 25th and 75th centiles for gestational age (appropriate weight for gestational age, [AFA]). Sex-specific median measurements of BMI, waist circumference, percentage body fat and height defined current anthropometric status, providing four groups for each measure: UFA-low or UFA-high and AFA-low or AFA-high. RESULTS: The UFA-high BMI group was more insulin-resistant than both low BMI groups (p < 0.04), but not the AFA-high BMI group. In contrast, plasma triglycerides and systolic BP were higher in the UFA-high than in all other groups (all p < 0.04). When characterised by body fatness, both high percentage (%) body fat groups had higher fasting [insulin] than low percentage (%) body fat groups (p < 0.03), and higher [total cholesterol] and [LDL cholesterol] than the UFA-low percentage (%) body fat group (p < 0.05). The UFA-high group had higher systolic and diastolic BP than all other groups (all at least p < 0.03). A similar pattern was observed when groups were characterised by waist circumference; however, current height status had no effect. CONCLUSIONS/INTERPRETATION: These data indicate that the "fetal origins" expression of the chronic disease phenotype is not dependent on birthweight alone, but on its interaction with subsequent fat accumulation, though not on attained height, in this cohort of young adults.
Subject(s)
Adipose Tissue/anatomy & histology , Blood Pressure/physiology , Body Mass Index , Hypertension/epidemiology , Infant, Low Birth Weight , Insulin Resistance/physiology , Adult , Blood Glucose/metabolism , Cholesterol/blood , Female , Growth/physiology , Humans , Infant, Newborn , Lipoproteins/blood , Male , Placenta/anatomy & histology , Pregnancy , South Africa , Triglycerides/bloodABSTRACT
AIMS/HYPOTHESIS: The association between CHD and insulin sensitivity (Si) measured by the euglycaemic insulin clamp has not been examined previously. Earlier studies found a relationship between CHD and elevated plasma insulin, an analysis that may have been confounded by co-determination of proinsulin, which has evolved as a stronger predictor of CHD. The aim was to determine the longitudinal relationships between Si, intact proinsulin, 32-33 split proinsulin, specific insulin and subsequent CHD. METHODS: This was a population-based cohort study of 815 men in Uppsala, Sweden, aged 70 years at baseline with a follow-up of up to 10 years. Baseline insulin sensitivity was determined by euglycaemic insulin clamp. Fasting proinsulin, 32-33 split proinsulin and specific insulin concentrations were analysed using specific two-site immunometric assays. CHD was taken as diagnosed, if stated (in the event of death) on the Cause of Death Registry, or for subjects hospitalised for the first time with CHD, if CHD was recorded in the Hospital-Discharge Registry. The associations were analysed using Cox's proportional hazards, presented as hazard ratios (HRs) with their 95% CIs for a one-SD increase in the predictor. RESULTS: In multivariate analysis, Si (HR:0.80, CI:0.65-0.97) adjusted for serum cholesterol, systolic blood pressure, fasting plasma glucose, BMI and smoking predicted CHD. Intact proinsulin (HR:1.18, CI:1.01-1.38), adjusted as the model above, predicted CHD, whereas 32-33 split proinsulin (HR:1.13, CI:0.95-1.35) or specific insulin (HR:1.07, CI:0.89-1.30) did not. CONCLUSIONS/INTERPRETATION: Insulin resistance measured by the euglycaemic insulin clamp predicts subsequent CHD in elderly men. Proinsulin provides a better prediction of CHD than insulin.
Subject(s)
Coronary Disease/epidemiology , Glucose Clamp Technique , Insulin/blood , Proinsulin/blood , Aged , Biomarkers/blood , Blood Glucose/metabolism , Body Mass Index , Coronary Disease/mortality , Follow-Up Studies , Health Surveys , Humans , Insulin/administration & dosage , Insulin/pharmacology , Male , Proportional Hazards Models , Survival Analysis , SwedenABSTRACT
Human adult diseases such as cardiovascular disease, hypertension, and type 2 diabetes have been epidemiologically linked to poor fetal growth and development. Male offspring of rat dams fed a low-protein (LP) diet during pregnancy and lactation develop diabetes with concomitant alterations in their insulin-signaling mechanisms. Such associations have not been studied in female offspring. The aim of this study was to determine whether female LP offspring develop diabetes in later life. Control and LP female offspring groups were obtained from rat dams fed a control (20% protein) or an isocaloric (8% protein) diet, respectively, throughout pregnancy and lactation. Both groups were weaned and maintained on 20% normal laboratory chow until 21 mo of age when they underwent intravenous glucose tolerance testing (IVGTT). Fasting glucose was comparable between the two groups; however, LP fasting insulin was approximately twofold that of controls (P < 0.02). Glucose tolerance during IVGTT was comparable between the two groups; however, LP peak plasma insulin at 4 min was approximately threefold higher than in controls (P < 0.001). LP plasma insulin area under the curve was 1.9-fold higher than controls (P < 0.02). In Western blots, both muscle protein kinase C-zeta expression and p110beta-associated p85alpha in abdominal fat were reduced (P < 0.05) in LPs. Hyperinsulinemia in response to glucose challenge coupled with attenuation of certain insulin-signaling molecules imply the development of insulin resistance in LP muscle and fat. These observations suggest that intrauterine protein restriction leads to insulin resistance in females in old age and, hence, an increased risk of type 2 diabetes.
Subject(s)
Diabetes Mellitus/embryology , Fetal Nutrition Disorders/physiopathology , Protein Deficiency/physiopathology , Aging , Animals , Diabetes Mellitus/physiopathology , Female , Gene Expression , Hyperinsulinism/embryology , Muscle Proteins/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Protein Kinase C/metabolism , Rats , Rats, Wistar , Signal Transduction/physiologyABSTRACT
Symptomatic oesophageal cancer is usually advanced and the prognosis poor. Lethality of symptomatic oesophageal cancer has motivated screening for these diseases earlier in their evolution, but reliable methods for early diagnosis remain elusive. We have demonstrated that dysregulated expression of minichromosome maintenance (MCM) proteins 2-7 is characteristic of early epithelial carcinogenesis, and that these key DNA replication initiation factors can be used as diagnostic markers for cervical and genito-urinary tract cancer. In this study, we investigated whether minichromosome maintenance protein 5 (Mcm5) can be used to detect oesophageal cancer cells in gastric aspirates. Two monoclonal antibodies raised against His-tagged human Mcm5 were used in a time-resolved immunofluorometric assay to measure Mcm5 levels in cells isolated from gastric aspirates of 40 patients undergoing gastroscopy for suspected or known oesophageal carcinoma or symptoms of dyspepsia. The test discriminated with high specificity and sensitivity between patients with and without oesophageal cancer (85% sensitivity (95% confidence interval (CI)=62-97%), 85% specificity (CI=66-96%)), as demonstrated by the large area under the receiver operating characteristics curve (0.93 (95% CI=0.85-0.99)). Elevated levels of Mcm5 in gastric aspirates are highly predictive of oesophageal cancer. This simple test for oesophageal cancer is readily automated with potential applications in primary diagnosis, surveillance and screening.
Subject(s)
Carcinoma/diagnosis , Carcinoma/genetics , Cell Cycle Proteins/analysis , Cell Cycle Proteins/biosynthesis , DNA Replication , Esophageal Neoplasms/diagnosis , Esophageal Neoplasms/genetics , Genetic Markers , Aged , Aged, 80 and over , Antibodies, Monoclonal , Automation , Biopsy, Needle , Cell Transformation, Neoplastic , DNA, Neoplasm/analysis , DNA-Binding Proteins , Diagnosis, Differential , Female , Fluorescent Antibody Technique , Gastroscopy , Humans , Male , Mass Screening , Middle Aged , Observer Variation , Schizosaccharomyces pombe Proteins , Sensitivity and Specificity , StomachABSTRACT
At birth, the endocrine pancreas must assume a glucoregulatory role if the neonate is to survive the transition from parenteral to enteral nutrition. In species like the horse, neonatal hypoglycaemia is common, which suggests that the glucoregulatory mechanisms are not always fully competent at birth. Hence, this study examined pancreatic beta cell function in newborn foals during nutritional adaptation over the first 10 days post partum. Over a 48 h period at three time intervals after birth (days 1-2, 5-6 and 9-10 post partum), the beta cell responses to suckling and to intravenous administration of glucose, arginine and saline were measured in seven normal pony foals. Basal plasma concentrations of proinsulin, but not insulin or glucose, increased significantly between days 1 and 10. Suckling caused a gradual increase in plasma glucose, which was accompanied by a significant increase in plasma insulin concentrations 15 min after the onset of suckling on days 5 and 9, but not day 1. There was no significant change in plasma proinsulin concentrations in response to suckling at any age. At all ages studied, glucose and arginine administration stimulated an increase in the plasma concentrations of insulin and proinsulin; these beta cell responses did not change significantly with postnatal age. The insulin responses to glucose were significantly greater than those of arginine at each time period. Glucose clearance was significantly slower on day 1 than subsequently. Proinsulin and glucose, but not insulin, concentrations decreased significantly after saline administration at all three ages. At each time period, there was a significant positive relationship between the plasma insulin and proinsulin concentrations, the slope of which was significantly shallower on days 1-2 than subsequently. These results show that equine beta cells are responsive to glucose and arginine and release both insulin and proinsulin during the immediate postnatal period. They also suggest that newborn foals may be insulin resistant on the first day after birth.
Subject(s)
Animals, Newborn/physiology , Horses/physiology , Insulin/metabolism , Islets of Langerhans/physiology , Proinsulin/metabolism , Animal Nutritional Physiological Phenomena , Animals , Arginine/pharmacology , Enteral Nutrition/veterinary , Glucose/pharmacology , Insulin Secretion , Islets of Langerhans/drug effects , Stimulation, ChemicalABSTRACT
AIMS/HYPOTHESIS: Type 2 diabetes risk is associated with low birth weight, rapid weight gain during childhood, and shorter stature and lower circulating IGF-I levels in adults. The largest variations in growth rates occur during the first postnatal years. We hypothesised that early postnatal variations in height and weight gain and IGF-I levels may be associated with risk markers for adult disease. METHODS: We measured the fasting insulin sensitivity (Homeostasis model) and insulin secretion post-oral glucose (insulinogenic index 0-30 min) in 851 normal 8-year-old children from a prospective birth cohort. We examined associations between size at birth, postnatal weight gain and circulating IGF-I levels with insulin sensitivity and secretion at 8 years of age. RESULTS: Fasting insulin sensitivity at 8 years was closely related to current BMI (r= -0.33, p<0.0005). Lower insulin sensitivity and higher BMI and waist circumference were all predicted by greater weight gain between birth to 3 years of age (all p<0.0005); lower birth weight was associated with reduced insulin sensitivity only in the highest current BMI tertile ( r=0.17, p=0.006). In contrast, lower insulin secretion was related to smaller size at birth ( p=0.01), independent of postnatal weight gain and insulin sensitivity. Lower insulin secretion was also independently related to shorter stature at 8 years of age relative to parental height ( p=0.047) and with lower plasma IGF-I levels at 5 years of age ( n=252, p=0.004). CONCLUSIONS/INTERPRETATION: Associations between lower birth weight and insulin resistance may be dependent on rapid weight gain during the early postnatal years. However, irrespective of postnatal weight gain, smaller size at birth, lower IGF-I levels and lower childhood height predicted reduced compensatory insulin secretion.
Subject(s)
Birth Weight/physiology , Growth/physiology , Insulin Resistance , Insulin-Like Growth Factor I/metabolism , Insulin/metabolism , Blood Glucose/analysis , Body Height/physiology , Body Mass Index , Body Surface Area , Child , Child, Preschool , Diabetes Mellitus, Type 2/etiology , Diabetes Mellitus, Type 2/physiopathology , Fasting/blood , Female , Glucose Tolerance Test/methods , Humans , Insulin/blood , Insulin Secretion , Insulin-Like Growth Factor I/chemistry , Longitudinal Studies , Male , Multivariate Analysis , Patient Selection , Prospective Studies , Random Allocation , Retrospective Studies , Risk Factors , Weight Gain/physiologyABSTRACT
Many adult diseases, including type 2 diabetes, hypertension and cardiovascular disease, are related to low birth weight. The mechanistic basis of this relationship is not known. To investigate the role of fetal undernutrition, we used a rat model of maternal protein restriction in which dams were fed a diet containing 80 g protein/kg (v. 200 g/kg in the control group) throughout gestation and lactation. Offspring were born smaller than controls and in adulthood developed diabetes, hyperinsulinaemia and tissue insulin resistance. To determine possible mechanisms of fetal programming, circulating levels of several hormones were measured in maternal plasma at gestational days 14, 17 and 21 and fetal plasma at gestational day 21. Several differences were noted at day 14, when glucose concentrations in maternal and feto-placental blood were raised significantly (P=0.04 and P=0.0001 respectively); insulin levels in the low-protein (LP) dams were raised (P=0.04), prolactin levels were raised (P=0.047) and progesterone levels were reduced (P=0.02). Circulating 17beta-oestradiol in the LP dams was raised by 35 % over those of the controls from day 17 to day 21 (P=0.008). A significant decrease in maternal leptin levels (P=0.004) was observed at gestation on day 21. Neither oestradiol nor leptin levels were altered in the fetal circulation at day 21. Maternal and fetal corticosterone levels were comparable with control levels, suggesting that they do not initiate the programming effects in this model. Our present results suggest that maternal protein restriction imposes changes in maternal levels of glucose, insulin, prolactin, progesterone, oestradiol and leptin; these changes could influence the programming of eventual adult disease in the developing fetus.
Subject(s)
Diet, Protein-Restricted/methods , Fetal Growth Retardation/physiopathology , Animals , Blood Glucose/analysis , Body Weight/physiology , Corticosterone/blood , Disease Models, Animal , Eating/physiology , Estradiol/blood , Fatty Acids, Nonesterified/blood , Female , Insulin/blood , Leptin/blood , Organ Size/physiology , Placenta/pathology , Pregnancy , Progesterone/blood , Prolactin/blood , Rats , Rats, Wistar , Triglycerides/blood , Weight Gain/physiologyABSTRACT
In rats, maternal anaemia during pregnancy causes hypertension in the adult offspring, although the mechanism is unknown. The present study investigated the renal morphology of adult rats born to mothers who were Fe-deficient during pregnancy. Rats were fed either a control (153 mg Fe/kg diet, n 7) or low-Fe (3 mg/kg diet, n 6) diet from 1 week before mating and throughout gestation. At delivery, the Fe-restricted (IR) mothers were anaemic; the IR pups were also anaemic and growth-retarded at 2 d of age. At 3 and 16 months, systolic blood pressure in the IR offspring (163 (sem 4) and 151 (sem 4) mmHg respectively, n 13) was greater than in control animals (145 (sem 3) and 119 (sem 4) mmHg respectively, n 15, P<0.05). At post mortem at 18 months, there was no difference in kidney weight between treatment groups, although relative kidney weight as a fraction of body weight in the IR offspring was greater than in control animals (P<0.05). Glomerular number was lower in the IR offspring (11.4 (sem 1.1) per 4 mm(2), n 13) compared with control rats (14.8 (sem 0.7), n 15, P<0.05). Maternal treatment had no effect on glomerular size, but overall, female rats had smaller and more numerous glomeruli per unit area than male rats. When all animals were considered, inverse relationships were observed between glomerular number and glomerular size (r-0.73, n 28, P<0.05), and glomerular number and systolic blood pressure at both 3 months (r-0.42, n 28, P<0.05) and 16 months of age (r-0.64, n 28, P<0.05). Therefore, in rats, maternal Fe restriction causes hypertension in the adult offspring that may be due, in part, to a deficit in nephron number.
Subject(s)
Anemia, Iron-Deficiency/pathology , Kidney/pathology , Prenatal Exposure Delayed Effects , Animals , Female , Fetal Growth Retardation/pathology , Hypertension/pathology , Iron, Dietary/administration & dosage , Kidney Glomerulus/pathology , Male , Organ Size , Pregnancy , Rats , Rats, WistarABSTRACT
We review the progress in testing the thrifty phenotype hypothesis. Many human epidemiological studies both by ourselves and others have confirmed and extended the original observations on which the hypothesis was based. We are not aware of any contradictory findings and we emphasise the strength of the association between birth weight and the subsequent development of the metabolic syndrome. We have worked extensively experimentally to test the hypothesis in a rat model in which pregnant and/or lactating dams are fed a diet moderately restricted in proteins. The range of programming effects that we have discovered in this example of fetal and early postnatal growth restriction is listed and includes changes in hormone receptors, signalling molecules and regulatory enzymes. We have shown the model to develop diabetes, the metabolic syndrome and signs of premature renal failure. We summarise these and other similarities between the phenotype of this model and human Type 2 diabetes and the metabolic syndrome. The number of insults during early development which can lead to a similar outcome is discussed and the suggestion is made that the early life response to stress is limited in its flexibility with outcomes including ageing and decreased longevity. Our preliminary results indicate that some MODY genes could suggest pathways whereby the changes occur and that epigenetic changes during development are involved. We conclude that the way is now clear to discover early human markers of programming by early life growth restriction and to use these to devise strategies for the prevention of Type 2 diabetes.
Subject(s)
Diabetes Mellitus/epidemiology , Embryonic and Fetal Development/physiology , Growth Disorders/physiopathology , Renal Insufficiency/epidemiology , Animals , Birth Weight , Diabetes Mellitus/etiology , Female , Humans , Infant, Newborn , Lactation , Metabolic Syndrome/epidemiology , Metabolic Syndrome/etiology , Models, Biological , Pregnancy , Rats , Renal Insufficiency/etiologyABSTRACT
Maternal diabetes during pregnancy is associated with excess fetal growth and increased fetal insulin production. We hypothesized that insulin propeptides (proinsulin and 32-33 split proinsulin) might be more robust indicators of chronic fetal overproduction of insulin. We examined insulin-like molecules in cord blood (ILM) (insulin, proinsulin, and 32-33 split proinsulin) in relation to birth weight, maternal glycemia, and cord glucose in 140 offspring of mothers with type 1 diabetes (ODM) and 49 offspring of mothers who did not have diabetes (CONTROL) as well as degradation of ILM in response to sampling conditions at birth. Insulin propeptides were abundant in cord blood, comprising 50% of ILM in CONTROL and 36% in ODM (P < 0.0001) and more resistant to degradation than insulin (P < 0.05). Concentrations of all three ILM were highly intercorrelated with median values 2- to 5-fold higher in ODM than CONTROL [e.g. median (range): insulin ODM 110 (60-217) pmol/liter; CONTROL 22 (15-37) pmol/liter; P < 0.0001]. In ODM, 32-33 split proinsulin and proinsulin were more closely related to birth weight (Spearman r for ILM: r(32-33 split)= 0.54; r(PROINSULIN): r = 0.54; r(INSULIN) = 0.40: r(32-33 split) and r(PROINSULIN) > r(INSULIN)P < 0.05) and fetal leptin (r(32-33 split)= 0.55; r(PROINSULIN); r = 0.54; r(INSULIN) = 0.22: r(32-33 split) and r(PROINSULIN) > r(INSULIN)P < 0.05) than insulin). By contrast, insulin was more closely related to cord glucose (r(32-33 split) = 0.15; r(PROINSULIN): r = 0.10; r(INSULIN) = 0.42: r(INSULIN) > r(32-33 split) and r(PROINSULIN)P < 0.05). In CONTROL, 32-33 split proinsulin was also more closely related to fetal leptin r(32-33 split)= 0.61; r(PROINSULIN): r = 0.29; r(INSULIN) = 0.33: r(32-33 split) > r(INSULIN)P < 0.05). In ODM, 32-33 split proinsulin and proinsulin have closer relationships to fetal growth and leptin concentrations at birth than insulin. Measurement of insulin propeptides may be advantageous in assessment of the influence of maternal hyperglycemia on the newborn.
Subject(s)
Diabetes Mellitus, Type 1/blood , Fetal Blood/chemistry , Insulin/blood , Pregnancy in Diabetics , Proinsulin/blood , Protein Precursors/blood , Birth Weight , Blood Glucose/analysis , Drug Stability , Female , Humans , Infant, Newborn , Male , Pregnancy , Sex CharacteristicsABSTRACT
AIMS/HYPOTHESIS: Defects in insulin secretion and insulin action, resulting in compensatory hyperinsulinaemia, are the major abnormalities in the development of Type 2 diabetes mellitus (Type 2 diabetes). The most frequently used conventional immunoreactive assays for insulin cross-react with proinsulin. In short-term studies (<5 years), proinsulin predicts the development of Type 2 diabetes. We studied, with a 27-year follow-up, the longitudinal relationships between intact proinsulin, 32-33 split proinsulin, specific and immunoreactive insulin (IRI), acute insulin response (AIR) after an intravenous glucose load and the development of Type 2 diabetes in a population-based cohort of 50-year-old men. METHODS: Fasting peptide concentrations were measured in plasma samples, stored since 1970-73 using specific two-site immunometric assays. IRI was measured at baseline using radioimmunoassay. Associations between development of Type 2 diabetes and predictor variables, were analysed with logistic regression. Results are shown as odds ratios (ORs) with their 95% confidence intervals (CIs) for a one standard deviation increase in a predictor variable. RESULTS: Cumulative incidence of Type 2 diabetes was 33% over 27 years of follow-up. Intact proinsulin (OR, 1.57, CI, 1.16-2.14), and 32-33 split proinsulin (OR, 1.70, CI, 1.20-2.39) were associated with development of Type 2 diabetes, independent of AIR, adjusted for BMI and fasting glucose, whereas specific insulin was not (OR, 1.31, CI, 0.98-1.77), nor was IRI (OR, 1.25, CI, 0.96-1.63). Proinsulin and AIR interacted in the development of Type 2 diabetes (p<0.05). CONCLUSION/INTERPRETATION: Proinsulin predicts the development of Type 2 diabetes mellitus over a 27-year period.
Subject(s)
Diabetes Mellitus, Type 2/epidemiology , Insulin/blood , Proinsulin/blood , Cohort Studies , Fasting/blood , Follow-Up Studies , Glucose Tolerance Test , Humans , Incidence , Male , Middle Aged , Odds Ratio , Osmolar Concentration , Prognosis , Protein Precursors/blood , Radioimmunoassay , Sweden/epidemiologyABSTRACT
Many epidemiological studies have now shown a strongly increased risk of developing type 2 diabetes and the metabolic syndrome in adults who as neonates showed signs of poor early (fetal and early postnatal) growth. The thrifty phenotype hypothesis was proposed to provide a conceptual and experimentally testable basis of these relationships. We have used protein restriction of rat dams, as a means to test this hypothesis. In vivo and in vitro studies of the growth-restricted offspring of such pregnancies have provided findings showing remarkable parallels with the human conditions. Permanent changes in the expression of regulatory proteins in liver, muscle and adipose tissue provide at least part of the explanation of the changes observed and offer potential markers for testing in the human context. These studies have also raised the question as to whether 'catch up' growth following early growth retardation may add to the risks posed by this early handicap. Male rats growth-retarded during fetal life and cross-fostered shortly after birth to normal lactating dams reach normal body and organ weights by weaning but have a reduced longevity. This finding raises the possibility that catch up growth, whilst potentially beneficial in the short term, may be detrimental to long-term survival. Human epidemiological studies may point in the same direction. Work by others on other models of early growth restriction have produced similar, although more limited, data. These findings raise the interesting possibility that the response to fetal stress, be it nutritional or other, may evoke a somewhat restricted and uniform pattern of adaptive response.
Subject(s)
Diabetes Mellitus, Type 1/epidemiology , Diabetes Mellitus, Type 2/epidemiology , Fetal Growth Retardation/epidemiology , Fetal Growth Retardation/physiopathology , Prenatal Nutritional Physiological Phenomena/physiology , Animals , Caloric Restriction , Diabetes Mellitus, Type 1/physiopathology , Diabetes Mellitus, Type 2/physiopathology , Female , Humans , Nutrition Disorders/epidemiology , Nutrition Disorders/physiopathology , Pregnancy , Risk FactorsABSTRACT
Telomeres, the non-coding sequences at the ends of chromosomes, in the absence of telomerase, progressively shorten with each cell division. Shortening of telomeres can induce cell cycle arrest and apoptosis. The aim of this study was to investigate age- and gender-related changes in telomere length in the rat and to detect possible tissue- specific rates of telomere shortening. Changes with age in telomere lengths were assessed by Southern blotting in the kidney, pancreas, liver, lung and brain of male and female rats. We determined the percentage of telomeres in various molecular size regions rather than measuring the average telomere length. The latter was unable to detect telomere shortening in the tissues. The percentage of short telomeres increased with age in the kidney, liver, pancreas and lung of both males and females, but not in the brain. Males had shorter telomeres than females in all organs analysed except the brain, where the lengths were similar. These findings indicate that telomeres shorten in the rat kidney, liver, pancreas and the lung in an age-dependent manner. These data also provide a novel mechanism for the gender-related differences in lifespan and suggest a tissue-specific regulation of telomere length during development and ageing in the rat.
Subject(s)
Aging/physiology , Telomere/metabolism , Animals , Animals, Newborn , Blotting, Southern , Brain/metabolism , DNA/genetics , Female , Kidney/metabolism , Liver/metabolism , Lung/metabolism , Male , Pancreas/metabolism , Rats , Rats, Wistar , Sex Factors , Telomere/genetics , Time FactorsABSTRACT
Studies of animal models were carried out to explore mechanisms that might underlie epidemiological findings linking indices of poor early (fetal and early postnatal) growth to an increased risk of developing poor glucose tolerance, including the metabolic syndrome, in adult life. Adult obesity was also seen to play an important role in adding to these risks. We proposed the 'thrifty phenotype' hypothesis to provide a conceptual and mechanistic framework that could be tested by experimentation in animal models. Our main approach has been to feed a reduced protein diet to pregnant and/or lactating rat dams as a means of reducing growth in the fetal and/or preweaning stages of pup growth. Animals were weaned onto either a normal diet or an obesity-inducing highly palatable, cafeteria-style diet. Alterations in intermediary metabolism were noted in the rats with early growth restriction, which provide support for our hypothesis and clues to the mechanism.
Subject(s)
Fetal Growth Retardation/metabolism , Metabolism/physiology , Prenatal Exposure Delayed Effects , Animals , Diet, Protein-Restricted/adverse effects , Female , Humans , Nutritional Status/physiology , Phenotype , Pregnancy , RatsABSTRACT
BACKGROUND: The epidemiologic data on heart failure are scarce. This study aimed at identifying predictors of left ventricular systolic dysfunction in a cohort of middle-aged men with a 20-year follow-up. METHODS: A population-based cohort of 431 50-year-old men was examined with blood pressure and anthropometric measurements together with lipid, glucose, and insulin determinations. A reinvestigation 20 years later also included echocardiography, ambulatory blood pressure monitoring, hyperinsulinemic euglycemic clamp, and oral glucose tolerance test. Sixteen subjects were found to have left ventricular systolic dysfunction at age 70 years, defined as an ejection fraction =0.40. A control group of 48 subjects matched on myocardial infarction, hypertension, diabetes, and use of cardiovascular medication, but with an ejection fraction >0.40, was used in a nested case-control analysis. RESULTS: At age 50 years, heart rate (P <.01), plasma proinsulin (P <.05), and the proportion of dihomogammalinolenic acid in serum cholesterol esters (P <.05) were increased and serum phosphate decreased (P <.01) in the subjects identified with left ventricular systolic dysfunction at age 70 years compared with controls. No major metabolic abnormalities were associated with left ventricular systolic dysfunction at age 70 years compared with controls. CONCLUSION: Factors associated with insulin resistance precede left ventricular systolic dysfunction independently of ischemic heart disease and hypertension after 20 years of follow-up.
Subject(s)
Metabolic Syndrome/genetics , Ventricular Dysfunction, Left/epidemiology , Age Factors , Aged , Blood Glucose/analysis , Case-Control Studies , Cohort Studies , Echocardiography , Follow-Up Studies , Glucose/metabolism , Heart Rate , Humans , Insulin Resistance/genetics , Male , Middle Aged , Proinsulin/blood , Risk Factors , Sweden/epidemiology , Ventricular Dysfunction, Left/diagnosis , Ventricular Dysfunction, Left/metabolismABSTRACT
An animal model of protein restriction during pregnancy and lactation with subsequent dietary fatty acid manipulation was used to investigate the association between poor early growth, defective unsaturated fatty acid handling, and later disease. Both control and early growth-restricted animals fed a diet rich in saturated fatty acids showed a doubling of the plasma insulin levels as well as a reduced degree of unsaturation in liver and skeletal muscle membrane phospholipids compared with animals fed diets rich in unsaturated fatty acids. The skeletal muscle of early growth-restricted animals weaned onto a saturated fat diet had reduced proportions of 22:6n-3 and increased proportions of 18:1n-9. This reduction in 22:6n-3 is similar to that observed in Pima Indians, a population with a high prevalence of type 2 diabetes.