Biomedical subjects

David B Dunger

Publications and source records attributed to David B Dunger.

67 records · Page 4Linked to original sources

PubMed2003

Hypoglycemia prevalence in prepubertal children with type 1 diabetes on standard insulin regimen: use of continuous glucose monitoring system.

OBJECTIVE: To determine hypoglycemia prevalence in prepubertal children on thrice (TID) and twice (BID) daily insulin regimens, using the Medtronic Minimed Continuous Glucose Monitoring System. RESEARCH DESIGN AND METHODS: Twenty-eight children aged <12 years (median 9.8, range 6.9-11.8) wore the sensor for three consecutive days and nights. Hypoglycemia was defined as glucose <60 mg/dl for >15 min. Data are expressed as the percentage of time period spent hypoglycemic. RESULTS: Hypoglycemia prevalence was 10.1% (mean 2.6 h. subject(-1) x day(-1)). Hypoglycemia was more common at night compared with daytime (18.81 vs. 4.4%, P < 0.001); 78 and 43% of subjects showed hypoglycemia on at least one night and two or more nights, respectively. Nocturnal episodes were prolonged (median 3.3 h) and asymptomatic (91% of episodes). Prevalence was greater between 0400 and 0730 h than between 2200 and 0400 h (25.5 vs. 15.4%, P < 0.001). On a TID compared with a BID regimen, nocturnal hypoglycemia prevalence was reduced, particularly between 0400-0730 h (22.9 vs. 27.4%, P = 0.005), whereas hypoglycemia the following morning (0730-1200 h) was greater (7.8 vs. 2.8%, P < 0.001). Nocturnal hypoglycemia risk was associated with decreasing age (by a factor of 0.6 for a year less in age), increased insulin dose (by 1.6 for an increase of 0.1 units. kg(-1) x day(-1)), insulin regimen (by 0.2 on a BID compared with a TID regimen), and increased weight standard deviation score (SDS) (by 2.7 for a one SDS rise). CONCLUSIONS: Use of standard insulin regimens results in high prevalence and large intraindividual variation in hypoglycemia, particularly at night. Independent risk factors for nocturnal hypoglycemia were younger age, greater daily insulin dose, insulin regimen, and increasing weight.

Blood Glucose Self-Monitoring↗

PubMed2003

Randomized cross-over trial of insulin glargine plus lispro or NPH insulin plus regular human insulin in adolescents with type 1 diabetes on intensive insulin regimens.

OBJECTIVE: To compare blood glucose control and incidence of nocturnal hypoglycemia in adolescents with type 1 diabetes on multiple injection regimens managed with either an insulin analog combination or NPH insulin plus regular human insulin. RESEARCH DESIGN AND METHODS: In a randomized cross-over study, 28 adolescents with type 1 diabetes on multiple injection therapy received either insulin glargine prebedtime plus lispro preprandially (LIS/GLAR) or NPH insulin prebedtime plus regular human insulin preprandially (R/NPH). During each 16-week treatment arm, subjects completed home blood glucose profiles, and at the end of each treatment arm, they were admitted for an overnight metabolic profile. A total of 25 subjects completed the study. RESULTS: Compared with R/NPH therapy, LIS/GLAR was associated with lower mean blood glucose levels (LIS/GLAR versus R/NPH): fasting (8.0 vs. 9.2 mmol/l, P < 0.0001), 2 h postbreakfast (8.1 vs. 10.7 mmol/l, P < 0.0005), prelunch (8.9 vs. 10.1 mmol/l, P < 0.01), and 2 h postlunch (8.0 vs. 9.5 mmol/l, P < 0.002). However, there was no difference in mean blood glucose levels before or after the evening meal. Incidence of nocturnal hypoglycemia on overnight profiles was 43% lower on LIS/GLAR compared with R/NPH therapy; however, there was no difference in rates of self-reported symptomatic hypoglycemia. Total insulin dose required to achieve target blood glucose control was lower on LIS/GLAR (1.16 IU/kg) compared with R/NPH therapy (1.26 IU/kg, P < 0.005), but there was no significant difference in HbA(1c) levels (LIS/GLAR versus R/NPH: 8.7 vs. 9.1%, P = 0.13). CONCLUSIONS: Combination therapy with insulin glargine plus lispro reduced the incidence of nocturnal hypoglycemia and was at least as effective as R/NPH insulin therapy in maintaining glycemic control in adolescents on multiple injection regimens.

Adolescent↗

PubMed2003

Poor prognosis of young adults with type 1 diabetes: a longitudinal study.

OBJECTIVE: To determine the role of early behavioral and psychological factors on later outcomes in young adults with childhood- or adolescent-onset type 1 diabetes. RESEARCH DESIGN AND METHODS: We conducted a longitudinal cohort study of patients recruited from the register of the young adult outpatient diabetes clinic, Oxford, U.K. A total of 113 individuals (51 male subjects) aged 17-25 years completed assessments, and 87 (77%) were reinterviewed as older adults (aged 28-37 years). Longitudinal assessments were made of glycemic control (HbA(1c)) and complications. Psychological state at baseline was assessed using the Present State Examination and self-report Symptom Checklist, with corresponding interview schedules administered at follow-up. RESULTS: There was no significant improvement between baseline and follow-up in mean HbA(1c) levels (8.5 vs. 8.6% in men, 9.3 vs. 8.7% in women). The proportion of individuals with serious complications (preproliferative or laser-treated retinopathy, proteinuria or more severe renal disease, peripheral neuropathy, and autonomic neuropathy) increased from 3-37% during the 11-year period. Women were more likely than men to have multiple complications (23 vs. 6%, difference 17%, 95% CI 4-29%, P = 0.02). Psychiatric disorders increased from 16 to 28% (20% in men, 36% in women at follow-up, difference NS), and 8% had psychiatric disorders at both assessments. Baseline psychiatric symptom scores predicted follow-up scores (beta = 0.32, SE [beta] 0.12, P = 0.008, 95% CI 0.09-0.56) and recurrent admissions with diabetic ketoacidosis (odds ratio 9.1, 95% CI 2.9-28.6, P < 0.0001). CONCLUSIONS: The clinical and psychiatric outcome in this cohort was poor. Psychiatric symptoms in later adolescence and young adulthood appeared to predict later psychiatric problems.

Adolescent↗

PubMed2003

Low IGF-I and elevated testosterone during puberty in subjects with type 1 diabetes developing microalbuminuria in comparison to normoalbuminuric control subjects: the Oxford Regional Prospective Study.

OBJECTIVE: To describe longitudinal variations in pubertal hormonal variables in subjects with and without microalbuminuria (MA). RESEARCH DESIGN AND METHODS: Blood samples collected annually from subjects recruited at diagnosis of type 1 diabetes and followed prospectively through puberty (median follow-up 9.3 years, range 4.7-12.8) were analyzed for total and free IGF-I, IGF binding protein-1, testosterone, sex hormone-binding globulin, and HbA(1c). A total of 55 subjects who developed MA (MA(+) group) were compared with 55 age-, sex-, and duration-matched control subjects who did not develop MA (MA(-) group). RESULTS: For female subjects, total IGF-I (MA(+) 1.2 mU/l vs. MA(-) 1.4 mU/l, P = 0.03) and free IGF-I levels (MA(+) 1,767 ng/l vs. MA(-) 2010 ng/l, P = 0.002) were lower, whereas the free androgen index (MA(+) 2.4 vs. MA(-) 2.0, P = 0.03) was higher in those with MA. These changes were less pronounced in male subjects. For both sexes, in a Cox model after adjusting for puberty, the presence of MA was associated with lower free IGF-I levels, higher testosterone standard deviation score (SDS), and poor glycemic control. We found that 22 of 55 case subjects (40%) developed persistent MA, whereas 33 (60%) had transient MA. In the persistent MA group compared with the transient and control groups, total IGF-I levels were lower (1.1 vs. 1.3 vs. 1.4 mU/l, P = 0.002) as were free IGF-I levels (1,370.9 vs. 1,907.3 vs. 1,886.7 ng/l, P < 0.001), whereas HbA(1c) levels were higher (11.8 vs. 10.3 vs. 9.9%, P < 0.001). CONCLUSIONS: Poor glycemic control and differences in IGF-I levels and androgens, particularly in female subjects, accompany development of MA at puberty. These differences may in part account for the sexual dimorphism in MA risk during puberty and could relate to disease progression.

Adolescent↗

PubMed2002

Insulin, insulin-like growth factor-I (IGF-I), IGF binding proteins, their biologic interactions, and colorectal cancer.

Secular changes and worldwide variations in incidence rates of colorectal cancer, along with results from twin and migrant studies, provide compelling evidence that environmental factors influence the risk of this disease. Among the most important of these factors are diet and associated factors, such as physical activity and body size. Recent data suggest that dietary and related factors may influence colorectal cancer risk via their effects on serum insulin concentrations and on the bioavailability of insulin-like growth factor-I (IGF-I). Epidemiologic studies have shown that IGF-I is positively associated with the risk of colorectal cancer, and experimental studies have shown that IGF-I has mitogenic and antiapoptotic actions on colorectal cancer cells. IGF-I bioactivity is regulated in part by its six binding proteins (IGFBP-1 to IGFBP-6); insulin inhibits the production of IGFBP-1 and perhaps IGFBP-2. As a result, chronically elevated fasting and postprandial insulin levels may lead to a decrease in circulating IGFBP-1 and IGFBP-2 concentrations and, consequently, an increase in IGF-I bioavailability. Insulin may also increase the circulating IGF-I/IGFBP-3 ratio by increasing hepatic growth hormone sensitivity. The increased IGF-I bioavailability may, over time, increase the risk of colorectal cancer. This new evidence for biologic interactions among insulin, IGF-I, and IGFBPs in the context of colorectal carcinogenesis provides a potential mechanism through which diet and associated factors may increase the risk of this cancer.

Animals↗

PubMed2002

Circulating concentrations of insulin-like growth factor-I and development of glucose intolerance: a prospective observational study.

BACKGROUND: Results of experimental and clinical studies suggest that insulin-like growth factor-I (IGF-I) and IGF binding protein-1 (IGFBP-1) could be important determinants of glucose homoeostasis. However, experimental models might also reflect compensatory and adaptive metabolic processes. We therefore prospectively examined the associations between circulating concentrations of IGF-I and IGFBP-1 and development of glucose tolerance. METHODS: Participants in this cohort study were a random sample of 615 normoglycaemic men and women aged 45-65 years. Participants underwent oral glucose tolerance testing based on WHO definitions and criteria in 1990-92 and 1994-96. At the baseline visit, we measured serum concentrations of IGF-I and IGFBP-1, and assessed the relation between these peptides and subsequent glucose intolerance. FINDINGS: At 4.5 years of follow-up, 51 (8%) of 615 participants developed impaired glucose tolerance or type-2 diabetes. After adjustment for correlates of IGF-I and risk factors for glucose intolerance, the odds ratio for risk of impaired glucose tolerance or type-2 diabetes for participants with IGF-I concentrations above the median (> or = 152 microg/L) compared with those with concentrations below the median (<152 microg/L) was 0.50 (0.26-0.95). Consistent with this finding, IGF-I also showed a significant inverse association with subsequent 2-h glucose concentrations, which was independent of correlates of IGF-I and risk factors for glucose tolerance (p for linear trend=0.026). We also found that this inverse association was independently modified by IGFBP-1 (p for interaction=0.011). INTERPRETATION: These data show that circulating IGF-I and its interaction with IGFBP-1 could be important determinants of glucose homoeostasis and provide further evidence for the possible protective role of IGF-I against development of glucose intolerance.

Aged↗

PubMed2002

Perinatal growth failure: the road to obesity, insulin resistance and cardiovascular disease in adults.

A continuum of increasing risk of adulthood diseases, such as cardiovascular disease, type 2 diabetes and hypertension, with decreasing size at birth is now well-reported and a number of different hypotheses have been proposed. Birthweight links with disease risk markers such as insulin resistance are apparent from childhood, particularly when low birthweight is followed by rapid postnatal weight gain and childhood obesity. Such growth patterns follow fetal growth restraint, associated with maternal-uterine factors such as primiparity, smoking, maternal genes or variations in maternal diet. The fetal metabolic and hormonal responses to intrauterine growth restraint and to rapid postnatal growth are likely to be key to the early pathogenesis of adulthood disease. Thrifty fetal genotypes may enhance these adaptations and improve perinatal survival but predispose to adulthood disease. Their historical selection could explain high prevalences of type 2 diabetes in some ethnic groups, and their identification could allow targeting of potential interventions.

Adult↗

PubMed2002

The somatotropic axis in short children born small for gestational age: relation to insulin resistance.

To determine whether hyperinsulinemia and reduced insulin sensitivity in individuals born small for gestational age (SGA) could be related to persisting abnormalities of the GH/IGF-I axis, we assessed overnight GH secretory profiles and measured fasting glucose, insulin, intact and 32,33 split proinsulin, and IGF-I levels in 16 short SGA children (age range 2.3-8.0 y) and in controls. Insulin sensitivity was calculated using the homeostasis model. Compared with short normal-birthweight controls (n = 7, age range 2.3-5.0 y), short SGA children had higher fasting insulin levels (means: 26.8 vs 20.6 pmol/L, p = 0.02), lower insulin sensitivity [means: 204 vs 284 %homeostasis model assessment (HOMA), p = 0.01], and higher beta cell function (112 vs 89 %HOMA, p = 0.04). SGA children also had lower levels of IGFBP-1 (87.0 vs 133.8, p = 0.04), but similar IGF-I levels (IGF-I SDS: -1.1 vs -1.7, p = 0.4). Compared with normal-height controls (n = 15, age range 5.6-12.1 y), SGA children had higher overnight GH secretion (GH maximum: 55.9 vs 39.6 mU/L, p = 0.01; mean: 13.1 vs 8.9, p = 0.004; minimum: 1.2 vs 0.6, p = 0.02). Interestingly, among SGA children, fasting insulin levels and insulin sensitivity were significantly related to overnight GH secretion (insulin sensitivity vs maximum GH: r = -0.68, p = 0.01; vs GH pulse amplitude r = -0.71, p = 0.007). The only hormone level significantly related to current height velocity was C-peptide (r = 0.75, p = 0.008). In conclusion, elevated fasting insulin levels and reduced insulin sensitivity in short SGA children was related to elevated levels of overnight GH secretion. We hypothesize that resistance to the somatotropic actions of GH and IGF-I in short SGA children may contribute directly to reduced insulin sensitivity.

Child↗

PubMed2002

Plasminogen activator inhibitor-1 in girls with precocious pubarche: a premenarcheal marker for polycystic ovary syndrome?

In both obese and nonobese women, polycystic ovary syndrome (PCOS) is essentially a disorder of hyperinsulinemic insulin resistance, and it may be heralded by precocious pubarche (PP; appearance of pubic hair in girls aged <8 y). The risk of progression from PP to PCOS is related to low birth weight, but there are no early biochemical markers of this risk. As increased plasminogen activator-inhibitor type 1 (PAI-1) activity (act) is an early marker of cardiovascular risk in PCOS, we have sought abnormalities in young girls with PP. In 33 young PP girls (age range 6-11 y), PAI-1-act was increased (mean + SEM: 15.6 +/- 1.5 IU/mL) compared with age-, sex-, and pubertal stage-matched controls (n = 13, 10.7 +/- 1.9, p < 0.05). PAI-1-act levels were inversely related to birth weight SD score (r = -0.33, p < 0.05), and PAI-1-act levels were therefore higher in PP girls with low birth weights (n = 14, 19.5 +/- 2.5 IU/mL) than normal birth weights (n = 19, 12.8 +/- 1.5, p < 0.01). During longitudinal observation in 10 PP girls (mean time interval 2.7 y), PAI-1-act levels in early puberty were positively related to postmenarcheal insulin levels (mean serum insulin SDS postoral glucose, r = 0.65, p < 0.05), and showed a similar relationship to postmenarcheal testosterone levels (r = 0.61, p = 0.06). Together with low birth weight, increased plasma PAI-1-act levels in early pubertal PP girls may indicate those girls with greater risk of developing hyperinsulinemic-hyperandrogenism features of PCOS.

Biomarkers↗

PubMed2002

Size at birth and early childhood growth in relation to maternal smoking, parity and infant breast-feeding: longitudinal birth cohort study and analysis.

There is remarkably wide variation in rates of infancy growth, however, its regulation is not well understood. We examined the relationship between maternal smoking, parity, and breast- or bottle-feeding to size at birth and childhood growth between 0 and 5 y in a large representative birth cohort. A total of 1,335 normal infants had weight, length/height, and head circumference measured at birth and on up to 10 occasions to 5 y old. Multilevel modeling (MLwiN) was used to analyze longitudinal growth data. Infants of maternal smokers were symmetrically small at birth (p < 0.0005) compared with infants of nonsmokers, however, showed complete catch-up growth over the first 12 mo. In contrast, infants of primiparous pregnancies were thin at birth (p < 0.0005), showed dramatic catch-up growth, and were heavier and taller than infants of nonprimiparous pregnancies from 12 mo onwards. Breast-fed infants were similar in size at birth than bottle-fed infants, but grew more slowly during infancy. Among infants who showed catch-up growth, males caught up more rapidly than females (p = 0.002). In conclusion, early postnatal growth rates are strongly influenced by a drive to compensate for antenatal restraint or enhancement of fetal growth by maternal-uterine factors. The mechanisms that signal catch-up or catch-down growth are unknown but may involve programming of appetite. The importance of nutrition on early childhood growth is emphasized by the marked difference in growth rates between breast- and bottle-fed infants. The sequence of fetal growth restraint and postnatal catch-up growth may predispose to obesity risk in this contemporary population.

Birth Weight↗

PubMed2002

Additive effects of insulin-sensitizing and anti-androgen treatment in young, nonobese women with hyperinsulinism, hyperandrogenism, dyslipidemia, and anovulation.

The endocrine-metabolic hallmarks of polycystic ovary syndrome are hyperinsulinism, hyperandrogenism, dyslipidemia, and anovulation. We hypothesized that dyslipidemia and anovulation in nonobese women with polycystic ovary syndrome are essentially secondary to the concerted effects of hyperandrogenism and insulin resistance. We tested this hypothesis by comparing the efficacy of anti-androgen (flutamide) or insulin-sensitizing (metformin) monotherapy to that of combined therapy in normalizing the endocrine-metabolic and anovulatory status of nonobese, young women with hyperinsulinemic hyperandrogenism. Thirty-one young women (mean age, 18.7 yr; body mass index, 21.9 kg/m(2); hirsutism score, 16; monthly ovulation rate monitored by weekly serum progesterone, 10%) were randomly assigned to receive once daily flutamide (250 mg; n = 10), metformin (1275 mg; n = 8), or combined flutamide- metformin therapy (n = 13) for 9 months. At baseline, there were no endocrine-metabolic differences among treatment groups. Compared with monotherapy, combined flutamide-metformin therapy resulted in greater improvements in insulin sensitivity, in testosterone, androstenedione, dehydroepiandrosterone sulfate, and triglyceride levels, and in low-density lipoprotein/high-density lipoprotein-cholesterol ratio (all P < 0.005). Monthly ovulation rates increased after 9 months to 75 and 92%, respectively, with metformin alone or with combined therapy, but were unimproved with flutamide alone. All treatments were well tolerated. In conclusion, combined anti-androgen and insulin-sensitizing treatment in young, nonobese women with hyperinsulinemic hyperandrogenism had additive benefits on insulin sensitivity, hyperandrogenemia, and dyslipidemia. The data from this small study suggest that dyslipidemia is secondary to excess androgen action in concert with the hyperinsulinemia associated with insulin resistance. In contrast, anovulation seems to be mainly attributable to insulin resistance and hyperinsulinemia.

Adult↗

PubMed2002

A longitudinal study of the effects of a gluten-free diet on glycemic control and weight gain in subjects with type 1 diabetes and celiac disease.

OBJECTIVE: To describe the longitudinal growth characteristics and glycemic control in type 1 diabetic children diagnosed with celiac disease and started on a gluten-free diet (GFD). RESEARCH DESIGN AND METHODS: Data on growth and glycemic control for 11 case subjects diagnosed with celiac disease (cd(+) group) and started on a GFD were collected prospectively, and two control subjects without celiac disease matched for age, sex, and duration of diabetes (cd(-) group) were selected for comparison. RESULTS: In the period between diagnosis of type 1 diabetes and start of a GFD in the cd(+) compared with the cd(-) group, BMI standard deviation score (SDS) was lower (-0.2 vs. 0.7, P = 0.015), as was HbA(1c) (8.9 vs. 9.8%, P = 0.002). In a regression model the cd(+) group had lower BMI SDS (P < 0.001) and lower HbA(1c) (P = 0.04), independent of other variables. On a GFD, BMI SDS increased by 12 months in the cd(+) group and then was no different than the cd(-) group (1.1 vs. 1.0, P = 0.11), whereas HbA(1c) improved further within case subjects compared with pre-GFD (8.9 vs. 8.3%, P = 0.002). On a GFD, case subjects in contrast to control subjects showed no deterioration in HbA(1c) during the years of puberty (8.3 vs. 10.0%, P = 0.022) CONCLUSIONS: In children with type 1 diabetes, untreated celiac disease resulted in lower BMI SDS and lower HbA(1c). Recovery of BMI SDS with a GFD was associated with further improvement in HbA(1c) as compared with pre-GFD, with no expected deterioration in glycemic control during puberty. These apparent clinical benefits need confirming by larger studies.

Adolescent↗

PubMedDate not supplied

No evidence for a major effect of two common polymorphisms of the catalase gene in type 1 diabetes susceptibility.

BACKGROUND: Type 1 diabetes (T1D) is a multifactorial disease, the genetic analysis of which has yielded few true positive linkage and association results. Replication of association in independent, large-sample studies is essential to further identify the genes involved in T1D. Two single nucleotide polymorphisms (SNPs) in the catalase gene have been reported to be associated with T1D. METHODS: Major effects of two SNPs, C1167T (rs769217) and C(-262)T (rs1001179), of the catalase gene on T1D susceptibility have been reported previously in Russians from Moscow. We genotyped C1167T and C(-262)T in large family (1642 families) and British case-control (3530 cases and 3930 controls) collections and tested for association with T1D. RESULTS: We found no evidence of an association between T1D and C1167T or C(-262)T in either the family or case-control collections, or for the D11S2008 microsatellite polymorphism in families. However, we did find limited statistical evidence of an association at C1167T in USA families (P = 0.033; RR for 1167C = 1.23, 95% CI = 1.02-1.49) and C(-262)T in UK families (P = 0.046; RR for (-262)C = 0.86, 95% CI = 0.75-0.99). CONCLUSION: We found no evidence for a major effect of C1167T or C(-262)T on T1D susceptibility in two large sample collections. Limited statistical evidence of an association at C1167T in USA families and C(-262)T in UK families was found, but these results are likely to be false positives. The previously reported association of these SNPs may also have been a false positive, or a population specific association in Russians from Moscow.

Base Sequence↗