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PubMed1986

Plasma catecholamines, dietary carbohydrate, and glucose intolerance: a comparison between young and old men.

Catecholamines play an important role in glucose homeostasis. This study was designed to determine whether circulating catecholamine changes in the elderly play a role in the glucose intolerance of aging and whether these changes are related to dietary carbohydrate intake. Plasma catecholamines (epinephrine and norepinephrine) and glucose were measured before and for 2 h after the administration of 100 g oral glucose in both 18 young (age, 18-39 yr) and 20 old (age, 60-82 yr) normal men during ad libitum home diet and after 3-day weight-maintaining, high or low carbohydrate formula diets in the Clinical Research Center. The elderly men had higher plasma norepinephrine levels before and after oral glucose than the young men even when eating matched formula diets. Plasma epinephrine levels were similar and decreased significantly after oral glucose in both groups. There was no relationship between catecholamine levels and degree of glucose tolerance. A high carbohydrate diet improved glucose tolerance in both old and young subjects. However, changes in dietary carbohydrates were not associated with consistent changes in plasma catecholamines. Therefore, we conclude that 1) glucose intolerance of aging cannot be explained by changes in plasma catecholamines, 2) the age-related increase in plasma norepinephrine is unrelated to dietary carbohydrate intake, and 3) there is no effect of age on suppression of plasma epinephrine after oral glucose administration.

Adolescent↗

PubMed2006

Adoptive transfer of regulatory NKT lymphocytes ameliorates non-alcoholic steatohepatitis and glucose intolerance in ob/ob mice and is associated with intrahepatic CD8 trapping.

The aim of this study was to determine the effect of adoptive transfer of regulatory natural killer T (NKT) lymphocytes on the metabolic disorder in leptin-deficient ob/ob mice, which feature depletion and defective function of NKT and CD4 lymphocytes. Leptin-deficient ob/ob mice were subjected to transplantation of 1 x 10(6) of either ob/ob or wild-type-derived NKT lymphocytes, or to transplantation of either ob/ob or wild-type-derived splenocytes. The effect on hepatic fat content was measured by magnetic resonance imaging (signal intensity index) and histology, using the steatohepatitis grading scale. The degree of glucose intolerance was measured by an oral glucose tolerance test (GTT). Adoptive transfer of wild-type or ob/ob-derived regulatory NKT cells led to a 12% decrease in hepatic fat content. A significant histological shift from macrosteatosis to microsteatosis was observed. Marked improvement in the GTT was noted in wild-type or ob/ob-derived NKT recipients. Metabolic effects were associated with a significant decrease in peripheral and intrahepatic CD4/CD8 lymphocyte ratios. Intrahepatic CD8 trapping was observed in all responders. Serum interleukin 10 levels decreased significantly. In conclusion, adoptive transfer of a relatively small number of regulatory NKT lymphocytes into ob/ob mice results in a significant reduction in hepatic fat content, a shift from macro to microsteatosis, and significant improvement in glucose intolerance. These effects were associated with decreased peripheral and intrahepatic CD4/CD8 ratios and decreased interleukin 10 levels. The results further support a role for regulatory NKT lymphocytes in the pathogenesis of non-alcoholic steatohepatitis in the leptin-deficient murine model.

Adoptive Transfer↗

PubMed2004

Diet-induced glucose intolerance in mice with decreased beta-cell ATP-sensitive K+ channels.

ATP-sensitive K+ channels (K(ATP) channels) control electrical activity in beta-cells and therefore are key players in excitation-secretion coupling. Partial suppression of beta-cell K(ATP) channels in transgenic (AAA) mice causes hypersecretion of insulin and enhanced glucose tolerance, whereas complete suppression of these channels in Kir6.2 knockout (KO) mice leads to hyperexcitability, but mild glucose intolerance. To test the interplay of hyperexcitability and dietary stress, we subjected AAA and KO mice to a high-fat diet. After 3 months on the diet, both AAA and KO mice converted to an undersecreting and markedly glucose-intolerant phenotype. Although Kir6.2 is expressed in multiple tissues, its primary functional consequence in both AAA and KO mice is enhanced beta-cell electrical activity. The results of our study provide evidence that, when combined with dietary stress, this hyperexcitability is a causal diabetic factor. We propose an "inverse U" model for the response to enhanced beta-cell excitability: the expected initial hypersecretion can progress to undersecretion and glucose-intolerance, either spontaneously or in response to dietary stress.

Animals↗

PubMedDate not supplied

Glucose intolerance and aging.

Glucose tolerance is known to decrease with advancing age. This decline begins in the third or fourth decade of life and is progressive throughout the entire adult life span. The primary cause of this age-related impairment in glucose metabolism results from tissue unresponsiveness to insulin. The plasma insulin response to glucose shows little change with age. Several factors, including decreased physical activity and decreased lean body mass, probably contribute to the insulin resistance. The aging process per se, however, appears to have its own deleterious effect on tissue sensitivity to insulin.

Adult↗

PubMed1995

Undiagnosed glucose intolerance in the community: the Isle of Ely Diabetes Project.

The Isle of Ely Diabetes Project is a prospective population-based study of the aetiology and pathogenesis of Type 2 diabetes mellitus. Between 1990 and 1992, 1156 subjects aged between 40 and 65 years underwent a standard 75 g oral glucose tolerance test (OGTT). A total of 1122 individuals who were not known to have diabetes completed the test and were classified according to WHO criteria; 51 subjects (4.5%) had previously undiagnosed diabetes and 188 (16.7%) had impaired glucose tolerance. The subjects with newly diagnosed glucose intolerance were significantly older, more obese, and shorter than those with normal glucose tolerance. Blood pressure, cholesterol, triglyceride, and LDL-cholesterol concentrations were elevated and HDL-cholesterol levels were lower among those with abnormal rather than normal glucose tolerance. In multiple regression analyses stratified by gender and including age, body mass index, and the waist-hip ratio as covariates, there were significant differences between those with normal and abnormal glucose intolerance in blood pressure, triglyceride, and HDL-cholesterol, but not total or LDL-cholesterol. In both male and female subjects, height had a significant independent negative association with the plasma glucose at 120 min after administration of oral glucose (standardized beta coefficient = -0.12, p < 0.01).

Adult↗

PubMed2004

Development of glucose intolerance in male transgenic mice overexpressing human glycogen synthase kinase-3beta on a muscle-specific promoter.

Glycogen synthase kinase-3 (GSK-3) protein levels and activity are elevated in skeletal muscle in type 2 diabetes, and inversely correlated with both glycogen synthase activity and insulin-stimulated glucose disposal. To explore this relationship, we have produced transgenic mice that overexpress human GSK-3beta in skeletal muscle. GSK-3beta transgenic mice were heavier, by up to 20% (P < .001), than their age-matched controls due to an increase in fat mass. The male GSK-3beta transgenic mice had significantly raised plasma insulin levels and by 24 weeks of age became glucose-intolerant as determined by a 50% increase in the area under their oral glucose tolerance curve (P < .001). They were also hyperlipidemic with significantly raised serum cholesterol (+90%), nonesterified fatty acids (NEFAs) (+55%), and triglycerides (+170%). At 29 weeks of age, GSK-3beta protein levels were 5-fold higher, and glycogen synthase activation (-27%), glycogen levels (-58%) and insulin receptor substrate-1 (IRS-1) protein levels (-67%) were significantly reduced in skeletal muscle. Hepatic glycogen levels were significantly increased 4-fold. Female GSK-3beta transgenic mice did not develop glucose intolerance despite 7-fold overexpression of GSK-3beta protein and a 20% reduction in glycogen synthase activation in skeletal muscle. However, plasma NEFAs and muscle IRS-1 protein levels were unchanged in females. We conclude that overexpression of human GSK-3beta in skeletal muscle of male mice resulted in impaired glucose tolerance despite raised insulin levels, consistent with the possibility that elevated levels of GSK-3 in type 2 diabetes are partly responsible for insulin resistance.

Animals↗

PubMed1988

Insulin infusions in infants of birthweight less than 1250 g and with glucose intolerance.

Fifteen preterm babies (mean gestation: 26.7 weeks; mean birthweight 860 g) with significant glucose intolerance were treated with insulin infusions. During the insulin infusions there was a significant increase in both the mean energy intake (60.8 +/- 25.1 cal/kg per day to 79.9 +/- 24.5 cal/kg per day; P less than 0.001) and the mean amount of intravenous dextrose tolerated (7.0 +/- 2.7 mg/kg per min to 9.2 +/- 2.6 mg/kg per min; P less than 0.01). The infusions were initiated at a mean postnatal age of 5.3 days (range: 2-12 days) and were continued for 1.5-17.5 days. Of the 998 blood glucose estimations performed during the insulin infusions, 28 (2.8%) were less than 2 mmol/l and 216 (21.6%) greater than 8 mmol/l. We conclude that continuous insulin infusion is a safe and effective way of managing glucose intolerance in very low birthweight infants, provided adequate means for continuous monitoring of blood glucose are available.

Blood Glucose↗

PubMed1993

The association of physical activity with obesity, fat distribution and glucose intolerance in Pima Indians.

The relationships between physical activity, obesity, fat distribution and glucose tolerance were examined in the Pima Indians who have the highest documented incidence of non-insulin-dependent diabetes. Fasting and 2-h post-load plasma glucose concentrations, body mass index, and waist-to-thigh circumference ratios were determined in 1054 subjects aged 15-59 years. Current (during the most recent calendar year) and historical (over a lifetime) leisure and occupational physical activity were determined by questionnaire. Current physical activity was inversely correlated with fasting and 2-h plasma glucose concentrations, body mass index and waist-to-thigh ratios for most sex-age groups even when diabetic subjects were excluded. Controlled for age, obesity and fat distribution, activity remained significantly associated with 2-h plasma glucose concentrations in males. In subjects aged 37-59 years, individuals with diabetes compared to those without reported significantly less leisure physical activity during the teenage years (median hours per week of activity, 9.1 vs 13.2 for men; 1.0 vs 2.2 for women). Controlled for body mass index, sex, age and waist-to-thigh ratio, subjects who reported low levels of historical leisure physical activity had a higher rate of diabetes than those who were more active. In conclusion, current physical activity was inversely related to glucose intolerance, obesity and central distribution of fat, particularly in males. Subjects with diabetes were currently less active and reported less historical physical activity than non-diabetic subjects. These findings suggest that activity may protect against the development of non-insulin-dependent diabetes both directly and through an influence on obesity and fat distribution.

Adipose Tissue↗

PubMed2002

The impact of impaired insulin release and insulin resistance on glucose intolerance after renal transplantation.

The current knowledge of the pathogenesis of post-transplant glucose intolerance is sparse. This study was undertaken to assess the relative importance of insulin secretion (ISec) and insulin sensitivity (IS) in the pathogenesis of post-transplant diabetes mellitus (PTDM), impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) after renal transplantation. An oral glucose tolerance test (OGTT) was performed in 167 non-diabetic recipients 10 wk after renal transplantation. Fasting, 1-h and 2-h insulin and glucose levels were used to estimate the insulin secretory response and IS. One year after transplantation 89 patients were re-examined with an OGTT including measurements of fasting and 2 h glucose. Ten weeks after transplantation the PTDM-patients had significantly lower ISec and IS than patients with IGT/IFG, who again had lower ISec and IS than those with normal glucose tolerance (NGT). One year later, a similar difference in baseline ISec was observed between the three groups, whereas baseline IS did not differ significantly. Patients who improved their glucose tolerance during the first year, were mainly characterized by a significantly greater baseline ISec, and they received a significantly higher median prednisolone dose at baseline with a subsequent larger dose reduction during the first year, than the patients who had their glucose tolerance unchanged or worsened. In conclusion, both impaired ISec and IS characterize patients with PTDM and IGT/IFG in the early course after renal transplantation. The presence of defects in insulin release, rather than insulin action, indicates a poor prognosis regarding later normalization of glucose tolerance.

Adolescent↗

PubMed1988

Classification and diagnostic criteria for diabetes mellitus and other categories of glucose intolerance.

Diabetes mellitus is composed of a heterogeneous group of disorders characterized by high blood glucose levels. Four major types of diabetes have been defined by the National Diabetes Data Group. Insulin-dependent diabetes (IDDM), also called type I diabetes, is characterized by abrupt clinical onset, insulinopenia, proneness to ketosis even in the basal state, and dependence on exogenous insulin to sustain life. Non-insulin-dependent diabetes (NIDDM), also called type II diabetes, may remain relatively asymptomatic for years. Insulin levels may be normal, lower than normal, or elevated as a consequence of insulin resistance. Ketosis is not part of the general clinical picture except in times of metabolic stress, although the classic complications of diabetes can be expected to develop in long-duration diabetics. Gestational diabetes (GDM) refers to the recognition of abnormal glucose intolerance in pregnancy, although unrecognized abnormal tolerance may indeed have predated the pregnancy. Rates of macrosomia are higher than in non-GDM pregnancies, but fetal mortality and congenital anomalies appear to be no greater than in the general population. Other types of diabetes include a number of diverse conditions in which glucose intolerance is a feature and in which it may be etiologically related. Impaired glucose tolerance (IGT) is a class that encompasses persons whose glucose tolerance is intermediate between normal and diabetic. These individuals do not manifest the microvascular complications of diabetes, but they appear to have higher rates of macrovascular disease associated with the known cardiovascular risk factors. Two statistical risk categories have also been defined that replace the older terms prediabetes, potential diabetes, and latent diabetes. Diabetes can be diagnosed by the presence of classical signs and symptoms of diabetes and unequivocally elevated blood glucose levels; by a fasting plasma glucose greater than or equal to 140 mg/dl; or by an abnormal oral glucose tolerance test, with a venous plasma glucose value greater than or equal to 200 mg/dl at 2 hours after 75 grams oral glucose, being a hallmark criterion for diabetes. For the latter two criteria, the abnormality should be reconfirmed at a later occasion before a definitive diagnosis of diabetes is made. The oral glucose tolerance test has been standardized at a 75-gram glucose (or carbohydrate equivalent) load, given in the morning after an overnight fast. Glucose should be determined for two hours after administration of the challenge.

Blood Glucose↗

PubMed2002

Abnormal cortisol metabolism and tissue sensitivity to cortisol in patients with glucose intolerance.

Recent evidence suggests that increased cortisol secretion, altered cortisol metabolism, and/or increased tissue sensitivity to cortisol may link insulin resistance, hypertension, and obesity. Whether these changes are important in type 2 diabetes mellitus (DM) is unknown. We performed an integrated assessment of glucocorticoid secretion, metabolism, and action in 25 unmedicated lean male patients with hyperglycemia (20 with type 2 diabetes and 5 with impaired glucose intolerance by World Health Organization criteria) and 25 healthy men, carefully matched for body mass index, age, and blood pressure. Data are mean +/- SE. Patients with hyperglycemia (DM) had higher HbA(1c) (6.9 +/- 0.2% vs. 6.0 +/- 0.1%, P < 0.0001) and triglycerides. Cortisol secretion was not different, as judged by 0900 h plasma cortisol and 24 h total urinary cortisol metabolites. However, the proportion of cortisol excreted as 5alpha- and 5beta-reduced metabolites was increased in DM patients. Following an oral dose of cortisone 25 mg, generation of plasma cortisol by hepatic 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD 1) was impaired in DM patients (area under the curve, 3617 +/- 281 nM.2 h vs. 4475 +/- 228; P < 0.005). In contrast, in sc gluteal fat biopsies from 17 subjects (5 DM and 12 controls) in vitro 11beta-HSD 1 activity was not different (area under the curve, 128 +/- 56% conversion.30 h DM vs. 119 +/- 21, P = 0.86). Sensitivity to glucocorticoids was increased in DM patients both centrally (0900 h plasma cortisol after overnight 250 micro g oral dexamethasone 172 +/- 16 nM vs. 238 +/- 20 nM, P < 0.01) and peripherally (more intense forearm dermal blanching following overnight topical beclomethasone; 0.56 +/- 0.92 ratio to vehicle vs. 0.82 +/- 0.69, P < 0.05). In summary, in patients with glucose intolerance, cortisol secretion, although normal, is inappropriately high given enhanced central and peripheral sensitivity to glucocorticoids. Normal 11beta-HSD 1 activity in adipose tissue with impaired hepatic conversion of cortisone to cortisol suggests that tissue-specific changes in 11beta-HSD 1 activity in hyperglycemia differ from those in primary obesity but may still be susceptible to pharmacological inhibition of the enzyme to reduce intracellular cortisol concentrations. Thus, altered cortisol action occurs not only in obesity and hypertension but also in glucose intolerance, and could therefore contribute to the link between these multiple cardiovascular risk factors.

Administration, Topical↗

PubMed1999

Glucose intolerance and 23-year risk of coronary heart disease and total mortality: the Honolulu Heart Program.

OBJECTIVE: The associations between glucose intolerance measured at the study entry date and the 23-year incidence of coronary heart disease (CHD), CHD mortality, and total mortality were examined at the Honolulu Heart Program. RESEARCH DESIGN AND METHODS: This prospective study followed a cohort of 8,006 Japanese-American men who were 45-68 years old and living on the island of Oahu, HI, in 1965. Baseline glucose was measured in a nonfasting state 1 h after a 50-g glucose load. History and use of medication for diabetes was obtained during an interview. The cohort was divided into four categories of glucose tolerance: low-normal, high-normal, asymptomatic hyperglycemia, and known diabetes. RESULTS: During the 23 years of follow-up, 864 incident cases of CHD, 384 deaths from CHD, and 2,166 total deaths occurred. The relative risks (RRs) were obtained using Cox proportional hazards modeling, with the low-normal category as a reference. The RRs were adjusted for age only, as well as for age, BMI, hypertension, cholesterol, triglycerides, smoking, alcohol, and a Japanese diet index. The age-adjusted and risk factor-adjusted RRs for all outcomes were significant for the asymptomatic hyperglycemic and known diabetes groups (P<0.05). The age-adjusted RRs for CHD incidence and total mortality were marginally significant in the high-normal group, but the RRs were not significant when adjusted for risk factors. CONCLUSIONS: These results suggest a dose-response relation of glucose intolerance at baseline with CHD incidence, CHD mortality, and total mortality, independent of other risk factors, in this cohort of middle-aged and older Japanese-American men.

Aged↗

PubMed1984

Glucose intolerance in sarcoma patients.

Twenty-seven otherwise healthy patients with localized sarcoma were examined to determine if glucose intolerance can be detected before the appearance of clinical signs of cachexia. No patient had lost weight or demonstrated severe malnutrition. Fasting plasma samples for glucose, insulin, glucagon, and free fatty acids (FFA) were obtained, and a standard intravenous glucose tolerance test performed. Glucose disappearance rate (K) was calculated between 5 and 60 minutes. K levels were compared to those of normal controls and to those of patients with more extensive cancer (statistics obtained from the literature). Levels for K were compared to tumor volume measurements following surgery. Fasting glucose, insulin, and glucagon levels were normal. Fasting FFA levels were slightly elevated. K levels for sarcoma patients were significantly lower than in control patients (P = 0.04), and higher than in patients with advanced cancer (P less than 0.0001). The subset of patients who weighed less than the ideal had a significantly lower K level than did the rest of the sarcoma population. K levels correlated inversely with tumor volume (r = -0.34; P = 0.04). These data indicate that mild glucose intolerance (reduction in clearance of a glucose load) occurs early in untreated sarcoma patients, is most prevalent in patients who maintain less than the ideal weight, correlates with tumor burden, and occurs before other signs of cachexia appear.

Adolescent↗

PubMed2005

Clustering of protective factors for glucose intolerance and insulin resistance: a cross-sectional study.

AIMS: A cluster of interrelated factors: a body mass index (BMI) < 25 kg/m(2), moderate exercise and alcohol intake, non-smoking and a favourable dietary pattern has been linked with markedly reduced risk of Type 2 diabetes. The aim of this study was to estimate the prevalence of a similar low-risk group in a sample of middle-aged Irish men and women, and determine whether this cluster is associated with a reduced risk of glucose intolerance (IFG and Type 2 diabetes according to ADA/WHO criteria) and insulin resistance [homeostasis model assessment (HOMA) score in upper quartile of distribution]. METHODS: A cross-sectional study involving a stratified random sample of 1018 general practice patients, aged 50-69 years. We defined a low-risk group based on the following variables: BMI < 25 kg/m(2); waist-hip ratio < 0.85 for women and 0.90 for men; never smoking status; participation in medium to high level of physical activity; light drinking (3.5-7 units of alcohol per week) and a 'prudent' dietary pattern. Valid data were available for glucose tolerance status and HOMA score and all exposure variables from 684 and 671 participants, respectively. RESULTS: A total of 7.5% of participants had none of the 'protective factors', 24.9% had one, 31.0% two, 23.3% three, 10.0% four, 3.0% five and 0.3% had six protective factors. In multivariate analyses the odds ratios for insulin resistance were 0.59, 0.48, 0.14 and 0.04 in persons with one, two, three and four or more low-risk factors, respectively, relative to those with none. Similar linear inverse trends were observed for glucose intolerance. CONCLUSIONS: The findings are consistent with an inverse linear relation between a cluster of core protective, lifestyle-related factors and the prevalence of both glucose intolerance and insulin resistance.

Aged↗

PubMed2003

Aberrant insulin-induced GLUT4 translocation predicts glucose intolerance in the offspring of a diabetic mother.

We examined the long-term effect of in utero exposure to streptozotocin-induced maternal diabetes on the progeny that postnatally received either ad libitum access to milk by being fed by control mothers (CM/DP) or were subjected to relative nutrient restriction by being fed by diabetic mothers (DM/DP) compared with the control progeny fed by control mothers (CM/CP). There was increased food intake, glucose intolerance, and obesity in the CM/DP group and diminished food intake, glucose tolerance, and postnatal growth restriction in the DM/DP group, persisting in the adult. These changes were associated with aberrations in hormonal and metabolic profiles and alterations in hypothalamic neuropeptide Y concentrations. By use of subfractionation and Western blot analysis techniques, the CM/DP group demonstrated a higher skeletal muscle sarcolemma-associated (days 1 and 60) and white adipose tissue plasma membrane-associated (day 60) GLUT4 in the basal state with a lack of insulin-induced translocation. The DM/DP group demonstrated a partial amelioration of this change observed in the CM/DP group. We conclude that the offspring of a diabetic mother with ad libitum postnatal nutrition demonstrates increased food intake and resistance to insulin-induced translocation of GLUT4 in skeletal muscle and white adipose tissue. This in turn leads to glucose intolerance and obesity at a later stage (day 180). Postnatal nutrient restriction results in reversal of this adult phenotype, thereby explaining the phenotypic heterogeneity that exists in this population.

Adipose Tissue↗

PubMed1980

Evaluation of enhanced glucagon sensitivity as the cause of glucose intolerance in acutely uremic rats.

These studies were undertaken to evaluate the possibility that increased hepatic glucose output, secondary to enhanced glucagon sensitivity, contributes to the glucose intolerance of acute uremia. In order to accomplish this, we determined the effect of an infusion of glucagon (6 ng/kg per min) on hepatic glucose output from isolated perfused livers of acutely uremic and sham-operated rats. Hepatic glucose output by livers from sham-operated rats more than doubled during glucagon infusion. In contrast, hepatic glucose output did not increase when livers of acutely uremic rats were perfused with glucagon. Furthermore, glycogen content did not fall nor did urea formation increas when livers from acutely uremic rats perfused with glucagon. On the other hand, dibutyryl cAMP infusion led to a similar increase in hepatic glucose output by livers from sham-operated and acutely uremic rats. Furthermore, urea formation increased and glycogen content decreased when livers from acutely uremic rats were perfused with dibutyryl cAMP. These results indicate that livers from acutely uremic rats exhibit a diminished responsiveness to glucagon-induced glycogenolysis and gluconeogenesis, but respond normally to dibutyryl cAMP. Thus, an increase in hepatic glucose output, secondary to enhanced glucagon sensitivity, does not appears to contribute to glucose intolerance in acutely uremic rats.

Acute Disease↗

PubMed2002

PAX6 mutation as a genetic factor common to aniridia and glucose intolerance.

A paired homeodomain transcription factor, PAX6, is a well-known regulator of eye development, and its heterozygous mutations in humans cause congenital eye anomalies such as aniridia. Because it was recently shown that PAX6 also plays an indispensable role in islet cell development, a PAX6 gene mutation in humans may lead to a defect of the endocrine pancreas. Whereas heterozygous mutations in islet-cell transcription factors such as IPF1/IDX-1/STF-1/PDX-1 and NEUROD1/BETA2 serve as a genetic cause of diabetes or glucose intolerance, we investigated the possibility of PAX6 gene mutations being a genetic factor common to aniridia and diabetes. In five aniridia and one Peters' anomaly patients, all of the coding exons and their flanking exon-intron junctions of the PAX6 gene were surveyed for mutations. The results of direct DNA sequencing revealed three different mutations in four aniridia patients: one previously reported type of mutation and two unreported types. In agreement with polypeptide truncation and a lack of the carboxyl-terminal transactivation domain in all of the mutated PAX6 proteins, no transcriptional activity was found in the reporter gene analyses. Oral glucose tolerance tests revealed that all of the patients with a PAX6 gene mutation had glucose intolerance characterized by impaired insulin secretion. Although we did not detect a mutation within the characterized portion of the PAX6 gene in one of the five aniridia patients, diabetes was cosegregated with aniridia in her family, and a single nucleotide polymorphism in intron 9 of the PAX6 gene was correlated with the disorders, suggesting that a mutation, possibly located in an uncharacterized portion of the PAX6 gene, can explain both diabetes and aniridia in this family. In contrast, the patient with Peters' anomaly, for which a PAX6 gene mutation is a relatively rare cause, showed normal glucose tolerance (NGT) and did not show a Pax6 gene mutation. Taken together, our present observations suggest that heterozygous mutations in the PAX6 gene can induce eye anomaly and glucose intolerance in individuals harboring these mutations.

Adolescent↗

PubMed2006

Reductions in caloric intake and early postnatal growth prevent glucose intolerance and obesity associated with low birthweight.

AIMS/HYPOTHESIS: Low birthweight (LBW) and rapid postnatal weight gain, or catch-up growth, are independent risk factors for the development of obesity and diabetes during adult life. Individuals who are both small at birth and have postnatal catch-up growth are at the highest risk. We hypothesised that dietary interventions designed to attenuate catch-up growth in LBW subjects may have long-term beneficial consequences. MATERIALS AND METHODS: We used our previously described mouse model of LBW-associated diabetes, created by restricting maternal food intake to 50% during the last week of gestation. Control (C) dams and dams that had been subjected to undernutrition (U) were then provided either chow ad libitum after delivery or 50% food restriction on a per-day basis from delivery until weaning. We designated the resulting four groups control-control (CC), undernutrition-control (UC), control-undernutriton (CU) and undernutrition-undernutrition (UU), indicating the prenatal and postnatal experimental conditions, respectively. Carbohydrate metabolism and adiposity were assessed prospectively in offspring until age 6 months. RESULTS: Males that were small at birth and exhibited early postnatal catch-up growth developed glucose intolerance and obesity by age 6 months. In contrast, LBW mice without catch-up growth (UU) remained smaller than controls (CC), and glucose intolerance and obesity was prevented. Similarly, mice with normal birthweight that had blunted catch-up growth (CU) were leaner and had better tolerance test than CC mice. Catch-up growth during the first week of life correlated better than birthweight with glucose, fat mass and glucose tolerance up to 6 months of age. CONCLUSIONS/INTERPRETATION: Prevention of early catch-up growth reversed the development of glucose intolerance and obesity in our mouse model of LBW-associated diabetes.

Diet, Reducing↗