Although the long-term health benefits of good glycemic control in patients with diabetes are well documented, shorter-term quality of life (QOL) and economic savings generally have been reported to ...be minimal or absent.
To examine short-term outcomes of glycemic control in type 2 diabetes mellitus (DM).
Double-blind, randomized, placebo-controlled, parallel trial.
Sixty-two sites in the United States.
A total of 569 male and female volunteers with type 2 DM.
After a 3-week, single-blind placebo-washout period, participants were randomized to diet and titration with either 5 to 20 mg of glipizide gastrointestinal therapeutic system (GITS) (n = 377) or placebo (n = 192) for 12 weeks.
Change from baseline in glucose and hemoglobin A1c (HbA1c) levels and symptom distress, QOL, and health economic indicators by questionnaires and diaries.
After 12 weeks, mean (+/-SE) HbA1c and fasting blood glucose levels decreased with active therapy (glipizide GITS) vs placebo (7.5% 0.1% vs 9.3%+/-0.1% and 7.0+/-0.1 mmol/L 126+/-2 mg/dL vs 9.3+/-0.2 mmol/L 168+/-4 mg/ dL, respectively; P<.001). Quality-of-life treatment differences (SD units) for symptom distress (+0.59; P<.001), general perceived health (+0.36; P= .004), cognitive functioning (+0.34; P=.005), and the overall visual analog scale (VAS) (+0.24; P=.04) were significantly more favorable for active therapy. Subscales of acuity (+0.38; P=.002), VAS emotional health (+0.35; P=.003), general health (+0.27; P=.01), sleep (+0.26; P=.04), depression (+0.25; P=.05), disorientation and detachment (+0.23; P= .05), and vitality (+0.22; P=.04) were most affected. Favorable health economic outcomes for glipizide GITS included higher retained employment (97% vs 85%; P<.001), greater productive capacity (99% vs 87%; P<.001), less absenteeism (losses = $24 vs $115 per worker per month; P<.001), fewer bed-days (losses = $1539 vs $1843 per 1000 person-days; P=.05), and fewer restricted-activity days (losses = $2660 vs $4275 per 1000 person-days; P=.01).
Improved glycemic control of type 2 DM is associated with substantial short-term symptomatic, QOL, and health economic benefits.
Endothelial function is impaired in patients with diabetes mellitus. However, the factors contributing to this defect are currently unknown. Hyperglycemia attenuates endothelium-dependent relaxation ...in normal rabbit arteries in vitro and rat arterioles in vivo. Accordingly, this study examined the effect of acute hyperglycemia on endothelium-dependent vasodilation in nondiabetic humans in vivo.
Endothelium-dependent vasodilation was assessed through brachial artery infusion of methacholine chloride both before and during 6 hours of local hyperglycemia (300 mg/dL) achieved by intra-arterial infusion of 50% dextrose. Forearm blood flow was determined by plethysmography. In a group of 10 subjects, there was a trend toward attenuated methacholine-mediated vasodilation during hyperglycemia compared with euglycemia (P=.07 by ANOVA; maximal response, 13.3+/-2.8 versus 14.7+/-1.5 mL x min(-1) x 100 mL(-1), respectively). In these subjects, the systemic serum insulin levels increased significantly during the dextrose infusion (P<.001). To eliminate the confounding vasoactive effects of insulin, the protocol was repeated during systemic infusion of octreotide (30 ng x kg(-1) x min(-1)) to inhibit pancreatic secretion of insulin. In these subjects (n=10), hyperglycemia significantly attenuated the forearm blood flow response to methacholine (P<.01 by ANOVA; maximal response, 16.9+/-2.5 before versus 12.7+/-1.8 mL x min(-1) x 100 mL(-1) during hyperglycemia). Methacholine-mediated vasodilation was not attenuated by an equimolar infusion of mannitol (P>.40), nor did hyperglycemia reduce endothelium-independent vasodilation to verapamil (P>.50).
Acute hyperglycemia impairs endothelium-dependent vasodilation in healthy humans in vivo. This finding suggests that elevated glucose may contribute to the endothelial dysfunction observed in patients with diabetes mellitus.
Previous studies have shown that Asian Indians (AIs) are insulin resistant and at high risk for developing diabetes and coronary heart disease, compared with Caucasians. To examine whether ...differences in body fat distribution contribute to this risk, 12 healthy AIs and 12 Caucasians matched for age and body mass index (BMI) underwent a 75-g oral glucose tolerance test, 2-h euglycemic hyperinsulinemic clamp, abdominal (L2-3) computed tomography scan, and fasting lipid and plasminogen activator inhibitor-1 (PAI-1) levels. Despite similar fasting plasma glucose levels, AIs exhibited fasting hyperinsulinemia (P = 0.001), higher glucose (P = 0.03) and insulin (P = 0.004) levels during the oral glucose tolerance test, and reduced glucose disposal rate (R(d)) (4.7 +/- 0.4 vs. 7.5 +/- 0.3 mg/kg per min, P < 0.0001) during the clamp. AIs had significantly lower high-density lipoprotein, higher low-density lipoprotein, and significantly higher PAI-1 levels (P = 0.01). Despite similar BMI, AIs had significantly greater total abdominal fat (P = 0.04) and visceral fat (P = 0.04). In all subjects, measures of fat mass were inversely correlated with R(d) during the clamp (r = -0.47 to -0.61, P < 0.01-0.001). Visceral fat mass was correlated with triglycerides, low-density lipoprotein, and high-density lipoprotein (P < 0.002-0.0001). PAI-1 was inversely correlated with R(d) in AIs (r = -0.70, P < 0.01) and not in Caucasians (r = -0.24, P = 0.44). For comparable BMI and age, healthy AIs have physiologic markers for insulin resistance, dyslipidemia, and increased cardiovascular risk, compared with Caucasians. Alterations in body fat distribution--particularly increased visceral fat--may contribute to these abnormalities.
Inbreeding depression refers to lower fitness among offspring of genetic relatives. This reduced fitness is caused by the inheritance of two identical chromosomal segments (autozygosity) across the ...genome, which may expose the effects of (partially) recessive deleterious mutations. Even among outbred populations, autozygosity can occur to varying degrees due to cryptic relatedness between parents. Using dense genome-wide single-nucleotide polymorphism (SNP) data, we examined the degree to which autozygosity associated with measured cognitive ability in an unselected sample of 4854 participants of European ancestry. We used runs of homozygosity-multiple homozygous SNPs in a row-to estimate autozygous tracts across the genome. We found that increased levels of autozygosity predicted lower general cognitive ability, and estimate a drop of 0.6 s.d. among the offspring of first cousins (P=0.003-0.02 depending on the model). This effect came predominantly from long and rare autozygous tracts, which theory predicts as more likely to be deleterious than short and common tracts. Association mapping of autozygous tracts did not reveal any specific regions that were predictive beyond chance after correcting for multiple testing genome wide. The observed effect size is consistent with studies of cognitive decline among offspring of known consanguineous relationships. These findings suggest a role for multiple recessive or partially recessive alleles in general cognitive ability, and that alleles decreasing general cognitive ability have been selected against over evolutionary time.
Inflammatory bowel disease 5 (IBD5) is a 250 kb haplotype on chromosome 5 that is associated with an increased risk of Crohn's disease in Europeans. The OCTN1 gene is centrally located on IBD5 and ...encodes a transporter of the antioxidant ergothioneine (ET). The 503F variant of OCTN1 is strongly associated with IBD5 and is a gain-of-function mutation that increases absorption of ET. Although 503F has been implicated as the variant potentially responsible for Crohn's disease susceptibility at IBD5, there is little evidence beyond statistical association to support its role in disease causation. We hypothesize that 503F is a recent adaptation in Europeans that swept to relatively high frequency and that disease association at IBD5 results not from 503F itself, but from one or more nearby hitchhiking variants, in the genes IRF1 or IL5. To test for evidence of recent positive selection on the 503F allele, we employed the iHS statistic, which was significant in the European CEU HapMap population (P = 0.0007) and European Human Genome Diversity Panel populations (P ≤ 0.01). To evaluate the hypothesis of disease-variant hitchhiking, we performed haplotype association tests on high-density microarray data in a sample of 1,868 Crohn's disease cases and 5,550 controls. We found that 503F haplotypes with recombination breakpoints between OCTN1 and IRF1 or IL5 were not associated with disease (odds ratio OR: 1.05, P = 0.21). In contrast, we observed strong disease association for 503F haplotypes with no recombination between these three genes (OR: 1.24, P = 2.6 × 10−8), as expected if the sweeping haplotype harbored one or more disease-causing mutations in IRF1 or IL5. To further evaluate these disease-gene candidates, we obtained expression data from lower gastrointestinal biopsies of healthy individuals and Crohn's disease patients. We observed a 72% increase in gene expression of IRF1 among Crohn's disease patients (P = 0.0006) and no significant difference in expression of OCTN1. Collectively, these data indicate that the 503F variant has increased in frequency due to recent positive selection and that disease-causing variants in linkage disequilibrium with 503F have hitchhiked to relatively high frequency, thus forming the IBD5 risk haplotype. Finally, our association results and expression data support IRF1 as a strong candidate for Crohn's disease causation.
New Findings
What is the topic of this review?
Tibetans have genetic adaptations that are hypothesized to underlie the distinct set of traits they exhibit at altitude.
What advances does it ...highlight?
Several adaptive signatures in the same genomic regions have been identified among Tibetan populations resident throughout the Qinghai‐Tibetan Plateau. Many highland Tibetans exhibit a haemoglobin concentration within the range expected at sea level, and this trait is associated with putatively adaptive regions harbouring the hypoxia‐inducible factor pathway genes EGLN1, EPAS1 and PPARA. Precise functional variants at adaptive loci and relationships to physiological traits, beyond haemoglobin concentration, are currently being examined in this population.
Some native Tibetan, Andean and Ethiopian populations have lived at altitudes ranging from 3000 to >4000 m above sea level for hundreds of generations and exhibit distinct combinations of traits at altitude. It was long hypothesized that genetic factors contribute to adaptive differences in these populations, and recent advances in genomics provide evidence that some of the strongest signatures of positive selection in humans are those identified in Tibetans. Many of the top adaptive genomic regions highlighted thus far harbour genes related to hypoxia sensing and response. Putatively adaptive copies of three hypoxia‐inducible factor pathway genes, EPAS1, EGLN1 and PPARA, are associated with sea‐level range, rather than elevated, haemoglobin concentration observed in many Tibetans at high altitude, and recent studies provide insight into some of the precise adaptive variants, timing of adaptive events and functional roles. While several studies in highland Tibetans have converged on a few hypoxia‐inducible factor pathway genes, additional candidates have been reported in independent studies of Tibetans located throughout the Qinghai‐Tibetan Plateau. Various aspects of adaptive significance have yet to be identified, integrated, and fully explored. Given the rapid technological advances and interdisciplinary efforts in genomics, physiology and molecular biology, careful examination of Tibetans and comparisons with other distinctively adapted highland populations will provide valuable insight into evolutionary processes and models for both basic and clinical research.
Human brain networks mediating interoceptive, behavioral, and cognitive aspects of glycemic control are not well studied. Using group independent component analysis with dual-regression approach of ...functional magnetic resonance imaging data, we examined the functional connectivity changes of large-scale resting state networks during sequential euglycemic-hypoglycemic clamp studies in patients with type 1 diabetes and nondiabetic controls and how these changes during hypoglycemia were related to symptoms of hypoglycemia awareness and to concurrent glycosylated hemoglobin (HbA1c) levels. During hypoglycemia, diabetic patients showed increased functional connectivity of the right anterior insula and the prefrontal cortex within the executive control network, which was associated with higher HbA1c. Controls showed decreased functional connectivity of the right anterior insula with the cerebellum/basal ganglia network and of temporal regions within the temporal pole network and increased functional connectivity in the default mode and sensorimotor networks. Functional connectivity reductions in the right basal ganglia were correlated with increases of self-reported hypoglycemic symptoms in controls but not in patients. Resting state networks that showed different group functional connectivity during hypoglycemia may be most sensitive to glycemic environment, and their connectivity patterns may have adapted to repeated glycemic excursions present in type 1 diabetes. Our results suggest that basal ganglia and insula mediation of interoceptive awareness during hypoglycemia is altered in type 1 diabetes. These changes could be neuroplastic adaptations to frequent hypoglycemic experiences. Functional connectivity changes in the insula and prefrontal cognitive networks could also reflect an adaptation to changes in brain metabolic pathways associated with chronic hyperglycemia.
The major factor limiting improved glucose control in type 1 diabetes is the significant increase in hypoglycemia associated with insulin treatment. Repeated exposure to hypoglycemia alters patients' ability to recognize the autonomic and neuroglycopenic symptoms associated with low plasma glucose levels. We examined brain resting state networks during the induction of hypoglycemia in diabetic and control subjects and found differences in networks involved in sensorimotor function, cognition, and interoceptive awareness that were related to chronic levels of glycemic control. These findings identify brain regions that are sensitive to variations in plasma glucose levels and may also provide a basis for understanding the mechanisms underlying the increased incidence of cognitive impairment and affective disorders seen in patients with diabetes.
To examine the effect of rosiglitazone on insulin resistance and blood pressure in patients with essential hypertension, classified based on abnormalities of their renin-angiotensin system.
A total ...of 24 hypertensive nondiabetic patients (age 58 +/- 6 years, BMI 30 +/- 5 kg/m2) were studied before and after rosiglitazone treatment. After 2 weeks off antihypertensive medication, subjects received a euglycemic-hyperinsulinemic clamp (40 mU. m(-2). min(-1)) with 6,6-2H2glucose infusion, ambulatory blood pressure monitoring, and blood tests for cardiovascular risk factors. Subjects were then placed on rosiglitazone (4 mg orally b.i.d.) and their usual antihypertensive medications (but not ACE inhibitors) for 16 weeks, and baseline tests were repeated.
There was no change in fasting plasma glucose (83 +/- 2 vs. 82 +/- 2 mg/dl, P = 0.60), but fasting insulin decreased (16.1 +/- 1.4 vs. 12.5 +/- 0.9 micro U/ml, P < 0.01). Total glucose disposal during the clamp increased (5.0 +/- 0.4 vs. 5.9 +/- 0.5 mg. kg(-1). min(-1), P < 0.001), with no change in suppression of hepatic glucose output. There were significant decreases in mean 24-h systolic (138 +/- 2 vs. 134 +/- 2 mmHg, P < 0.02) and diastolic (85 +/- 2 vs. 80 +/- 2 mmHg, P < 0.0001) blood pressure, and the decline in systolic blood pressure was correlated with the improvement in insulin sensitivity (r = 0.59, P < 0.005). Triglycerides (135 +/- 16 vs. 89 +/- 8 mg/dl, P < 0.01), LDL cholesterol (129 +/- 6 vs. 122 +/- 8 mg/dl, P = 0.18), and HDL cholesterol (51 +/- 3 vs. 46 +/- 3 mg/dl, P < 0.02) all decreased, with no change in the LDL-to-HDL ratio. Plasminogen activator inhibitor-1 and C-reactive protein also declined significantly.
Rosiglitazone treatment of nondiabetic hypertensive patients improves insulin sensitivity, reduces systolic and diastolic blood pressure, and induces favorable changes in markers of cardiovascular risk. Insulin sensitizers may provide cardiovascular benefits when used in the treatment of patients with hypertension.
The effect of metformin on glucose metabolism was examined in eight obese (percent ideal body weight, 151 +/- 9%) and six lean (percent ideal body weight, 104 +/- 4%) noninsulin-dependent diabetic ...(NIDD) subjects before and after 3 months of metformin treatment (2.5 g/day). Fasting plasma glucose (11.5-8.8 mmol/L), hemoglobin-A1c (9.8-7.7%), oral glucose tolerance test response (20.0-17.0 mmol/L; peak glucose), total cholesterol (5.67-4.71 mmol/L), and triglycerides (2.77-1.52 mmol/L) uniformly decreased (P less than 0.05-0.001) after metformin treatment; fasting plasma lactate increased slightly from baseline (1.4 to 1.7 mmol/L; P = NS). Body weight decreased by 5 kg in obese NIDD subjects, but remained constant in lean NIDD. Basal hepatic glucose production declined in all diabetics from 83 to 61 mg/m2.min (P less than 0.01), and the decrease correlated (r = 0.80; P less than 0.01) closely with the fall in fasting glucose concentration. Fasting insulin (115 to 79 pmol/L) declined (P less than 0.05) after metformin. During a 6.9 mmol/L hyperglycemic clamp, glucose uptake increased in every NIDD subject (113 +/- 15 to 141 +/- 12 mg/m2.min; P less than 0.001) without a change in the plasma insulin response. During a euglycemic insulin clamp, total glucose uptake rose in obese NIDD subjects (121 +/- 10 to 146 +/- 9 mmol/m2.min; P less than 0.05), but decreased slightly in lean NIDD (121 +/- 10 to 146 +/- 0.5; P = NS). Hepatic glucose production was suppressed by more than 80-90% in all insulin clamp studies before and after metformin treatment. In conclusion, metformin lowers the fasting plasma glucose and insulin concentrations, improves oral glucose tolerance, and decreases plasma lipid levels independent of changes in body weight. The improvement in fasting glucose results from a reduction in basal hepatic glucose production. Metformin per se does not enhance tissue sensitivity to insulin in NIDD subjects. The improvement in glucose metabolism under hyperglycemic, but not euglycemic, conditions suggests that metformin augments glucose-mediated glucose uptake. Metformin has no stimulatory effect on insulin secretion.
PDF
