scholarly journals Fine-mapping diabetes-related traits, including insulin resistance, in heterogeneous stock rats

2012 ◽  
Vol 44 (21) ◽  
pp. 1013-1026 ◽  
Author(s):  
Leah C. Solberg Woods ◽  
Katie L. Holl ◽  
Daniel Oreper ◽  
Yuying Xie ◽  
Shirng-Wern Tsaih ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Fine Mapping ◽  
Mixed Model ◽  
Area Under The Curve ◽  
Penalized Regression ◽  
Chromosome 1 ◽  
Linkage Disequilibrium Mapping ◽  
Heterogeneous Stock

Type 2 diabetes (T2D) is a disease of relative insulin deficiency resulting from both insulin resistance and beta cell failure. We have previously used heterogeneous stock (HS) rats to fine-map a locus for glucose tolerance. We show here that glucose intolerance in the founder strains of the HS colony is mediated by different mechanisms: insulin resistance in WKY and an insulin secretion defect in ACI, and we demonstrate a high degree of variability for measures of insulin resistance and insulin secretion in HS rats. As such, our goal was to use HS rats to fine-map several diabetes-related traits within a region on rat chromosome 1. We measured blood glucose and plasma insulin levels after a glucose tolerance test in 782 male HS rats. Using 97 SSLP markers, we genotyped a 68 Mb region on rat chromosome 1 previously implicated in glucose and insulin regulation. We used linkage disequilibrium mapping by mixed model regression with inferred descent to identify a region from 198.85 to 205.9 that contains one or more quantitative trait loci (QTL) for fasting insulin and a measure of insulin resistance, the quantitative insulin sensitivity check index. This region also encompasses loci identified for fasting glucose and Insulin_AUC (area under the curve). A separate <3 Mb QTL was identified for body weight. Using a novel penalized regression method we then estimated effects of alternative haplotype pairings under each locus. These studies highlight the utility of HS rats for fine-mapping genetic loci involved in the underlying causes of T2D.

scholarly journals Fine-mapping a locus for glucose tolerance using heterogeneous stock rats

2010 ◽  
Vol 41 (1) ◽  
pp. 102-108 ◽  
Author(s):  
Leah C. Solberg Woods ◽  
Katie Holl ◽  
Michael Tschannen ◽  
William Valdar
Keyword(s):  
Glucose Tolerance ◽  
Family Structure ◽  
Fine Mapping ◽  
Complex Traits ◽  
Mixed Model ◽  
Average Distance ◽  
Tolerance Test ◽  
Chromosome 1 ◽  
Heterogeneous Stock ◽  
Mixed Model Analysis

Heterogeneous stock (HS) animals provide the ability to map quantitative trait loci at high resolution [<5 Megabase (Mb)] in a relatively short time period. In the current study, we hypothesized that the HS rat colony would be useful for fine-mapping a region on rat chromosome 1 that has previously been implicated in glucose regulation. We administered a glucose tolerance test to 515 HS rats and genotyped these animals with 69 microsatellite markers, spaced an average distance of <1 Mb apart, on a 67 Mb region of rat chromosome 1. Using regression modeling of inferred haplotypes based on a hidden Markov model reconstruction and mixed model analysis in which we accounted for the complex family structure of the HS, we identified one sharp peak within this region. Using positional bootstrapping, we determined the most likely location of this locus is from 205.04 to 207.48 Mb. This work demonstrates the utility of HS rats for fine-mapping complex traits and emphasizes the importance of taking into account family structure when using highly recombinant populations.

scholarly journals Impaired β-Cell Function in Human Aging: Response to Nicotinic Acid-Induced Insulin Resistance

2006 ◽  
Vol 91 (9) ◽  
pp. 3303-3309 ◽  
Author(s):  
Annette M. Chang ◽  
Marla J. Smith ◽  
Andrzej T. Galecki ◽  
Cathie J. Bloem ◽  
Jeffrey B. Halter
Keyword(s):  
Insulin Resistance ◽  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Older People ◽  
Nicotinic Acid ◽  
Area Under The Curve ◽  
Disposition Index ◽  
Human Aging ◽  
Β Cell ◽  
Cell Sensitivity

Abstract Context: Glucose tolerance declines with age and may involve impaired β-cell sensitivity to glucose and β-cell compensation for insulin resistance. Objective: We investigated β-cell sensitivity to glucose and β-cell compensation for nicotinic acid-induced insulin resistance in young (age &lt;35 yr) people with normal glucose tolerance (NGT) and old (age &gt;60 yr) people with NGT and impaired glucose tolerance (IGT). Design/Patients/Setting/Intervention: Fifteen young NGT, 16 old NGT, and 14 old IGT were randomized to 2-wk treatment with nicotinic acid or placebo in a double-blind, crossover study in a university medical setting. At the end of each treatment period, participants had a frequently sampled iv glucose tolerance test and ramp clamp, in which insulin secretion rates (ISR) were determined in response to a matched 5–10 mm glucose stimulus. Main Outcome Measures: Insulin sensitivity (SI), acute insulin response to iv glucose (AIRg), and disposition index (AIRg × SI, or β-cell compensation for insulin resistance) from frequently sampled iv glucose tolerance testing, and ISR area under the curve (or β-cell sensitivity to glucose) from ramp clamp were determined. Results: Progressive impairments in insulin secretion as assessed by AIRg, disposition index, and ISR area under the curve were identified in older people with NGT, with more marked defects in older people with IGT. Nicotinic acid treatment significantly reduced SI in all groups. β-Cell compensation for nicotinic acid-induced insulin resistance was incomplete in all three groups, with greater defects in the two older groups. Conclusions: Human aging is associated with impaired β-cell sensitivity to glucose and impaired β-cell compensation to insulin resistance.

Effects of maternal periconceptional undernutrition in sheep on offspring glucose–insulin axis function into adulthood

2020 ◽  
pp. 1-7
Author(s):  
Mark H. Oliver ◽  
Frank H. Bloomfield ◽  
Amita Bansal ◽  
Hui Hui Phua ◽  
Eric B. Thorstensen ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Protein Expression ◽  
Insulin Signalling ◽  
Area Under The Curve ◽  
Late Gestation ◽  
Maternal Undernutrition ◽  
Kinase C ◽  
First Phase Insulin Secretion ◽  
Protein Kinase C Zeta

Abstract Maternal periconceptional undernutrition (PCUN) affected fetal pancreatic maturation in late gestation lambs and impaired glucose tolerance in 10-month-old sheep. To examine the importance of the timing of maternal undernutrition around conception, a further cohort was born to PCUN ewes [undernourished for 61 d before conception (PreC), 30 d after conception (PostC), or 61 d before until 30 d after conception (PrePostC)], or normally fed ewes (Control) (n = 15–20/group). We compared glucose tolerance, insulin secretion, and sensitivity at 36 months of age. We also examined protein expression of insulin signalling proteins in muscle from these animals and in muscle from a fetal cohort (132 d of gestation; n = 7–10/group). Adult PostC and PrePostC sheep had higher glucose area under the curve than Controls (P = 0.07 and P = 0.02, respectively), whereas PreC sheep were similar to Controls (P = 0.97). PostC and PrePostC had reduced first-phase insulin secretion compared with Control (P = 0.03 and P = 0.02, respectively). PreC was similar to Control (P = 0.12). Skeletal muscle SLC2A4 protein expression in PostC and PrePostC was increased 19%–58% in fetuses (P = 0.004), but decreased 39%–43% in adult sheep (P = 0.003) compared with Controls. Consistent with this, protein kinase C zeta (PKCζ) protein expression tended to be increased in fetal (P = 0.09) and reduced in adult (P = 0.07) offspring of all PCUN ewes compared with Controls. Maternal PCUN alters several aspects of offspring glucose homeostasis into adulthood. These findings suggest that maternal periconceptional nutrition has a lasting impact on metabolic homeostasis of the offspring.

scholarly journals Interplay of Dinner Timing and MTNR1B Type 2 Diabetes Risk Variant on Glucose Tolerance and Insulin Secretion: A Randomized Crossover Trial

2022 ◽  
Author(s):  
Marta Garaulet ◽  
Jesus Lopez-Minguez ◽  
Hassan S Dashti ◽  
Céline Vetter ◽  
Antonio Miguel Hernández-Martínez ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Area Under The Curve ◽  
Serum Levels ◽  
Postprandial Glucose ◽  
Oral Glucose ◽  
Elevated Concentration ◽  
Endogenous Melatonin

<strong>Objective: </strong>We tested whether the concurrence of food intake and elevated concentration of endogenous melatonin, as occurs in late eating, results in impaired glucose control, in particular in carriers of the type 2 diabetes-associated G allele in the melatonin-receptor-1-b gene (<i>MTNR1B</i>).<strong> </strong> <p><strong>Research Design and Methods:</strong> In a Spanish natural late eating population, a randomized, cross-over study design was performed, following an 8-h fast. Each participant <strong>(n=845) </strong>underwent two evening 2-h 75g oral glucose tolerance tests (OGTT): an early condition scheduled 4 hours prior to habitual bedtime <strong>(“early dinner-timing”)</strong>, and a late condition scheduled 1 hour prior to habitual bedtime <strong>(“late dinner-timing”)</strong>, simulating an early and a late dinner timing, respectively.<strong> </strong>Differences in postprandial glucose and insulin responses were determined using incremental area under the curve (AUC) calculated by the trapezoidal method between <strong>early and late dinner-timing.</strong><strong></strong></p> <p><strong>Results:</strong> <strong>Melatonin serum levels were </strong>3.5-fold <strong>higher in the late <i>vs. </i>early condition, with late dinner-timing resulting in </strong>6.7% <strong>lower insulin</strong> <strong>area-under-the-curve (AUC) and </strong>8.3%<strong> higher glucose</strong> <strong>AUC. In the late condition<i> MTNR1B</i> G-allele carriers had lower glucose tolerance than non-carriers. Genotype differences in glucose tolerance were attributed to reductions in </strong>β-cell <strong>function (<i>P<sub>int</sub></i><sub> </sub>AUCgluc=0.009, <i>P<sub>int</sub></i><sub> </sub>CIR=0.022, <i>P<sub>int </sub></i>DI=0.018).</strong></p> <p><strong>Conclusions:</strong> <strong>Concurrently high endogenous melatonin and carbohydrate intake, as typical for late eating, impair glucose tolerance, especially in <i>MTNR1B</i> G-risk-allele carriers<i>, </i>attributable to insulin secretion defects.</strong></p>

scholarly journals Dual Mechanism for Type-2 Diabetes Resolution after Roux-en-Y Gastric Bypass

2009 ◽  
Vol 75 (6) ◽  
pp. 498-503 ◽  
Author(s):  
Edward Lin ◽  
S. Scott Davis ◽  
Jahnavi Srinivasan ◽  
John F. Sweeney ◽  
Thomas R. Ziegler ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Weight Loss ◽  
Gastric Bypass ◽  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Cell Function ◽  
Β Cell ◽  
Peripheral Insulin Resistance

Resolution of Type-2 diabetes mellitus (DM) after weight loss surgery is well documented, but the mechanism is elusive. We evaluated the glucose-insulin metabolism of patients undergoing a Roux-en-Y gastric bypass (RYGB) using the intravenous glucose tolerance test (IVGTT) and compared it with patients who underwent laparoscopic adjustable gastric band (AB) placement. Thirty-one female patients (age range, 20 to 50 years; body mass index, 47.2 kg/m2) underwent RYGB. Nine female patients underwent AB placement and served as control subjects. All patients underwent IVGTT at baseline and 1 month and 6 months after surgery. Thirteen patients undergoing RYGB and one patient undergoing AB exhibited impaired glucose tolerance or DM defined by the American Diabetes Association. By 6 months post surgery, diabetes was resolved in all but one patient undergoing RYGB but not in the patient undergoing AB. Patients with diabetes undergoing RYGB demonstrated increased insulin secretion and β-cell responsiveness 1 month after surgery and continued this trend up to 6 months, whereas none of the patients undergoing AB had changes in β-cell function. Both patients undergoing RYGB and those undergoing AB demonstrated significant weight loss (34.6 and 35.0 kg/m2, respectively) and improved insulin sensitivity at 6 months. RYGB ameliorates DM resolution in two phases: 1) early augmentation of beta cell function at 1 month; and 2) attenuation of peripheral insulin resistance at 6 months. Patients undergoing AB only exhibited reduction in peripheral insulin resistance at 6 months but no changes in insulin secretion.

scholarly journals The Finnish Diabetes Risk Score Is Associated with Insulin Resistance and Progression towards Type 2 Diabetes

2009 ◽  
Vol 94 (3) ◽  
pp. 920-926 ◽  
Author(s):  
Peter E. H. Schwarz ◽  
Jiang Li ◽  
Manja Reimann ◽  
Alta E. Schutte ◽  
Antje Bergmann ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Cohort Study ◽  
Glucose Tolerance ◽  
Area Under The Curve ◽  
Diabetes Risk ◽  
Operating Characteristics ◽  
Cross Sectional Survey ◽  
Cross Sectional

Abstract Objective: The Finnish Diabetes Risk Score (FINDRISC) questionnaire is a practical screening tool to estimate the diabetes risk and the probability of asymptomatic type 2 diabetes. In this study we evaluated the usefulness of the FINDRISC to predict insulin resistance in a population at increased diabetes risk. Design: Data of 771 and 526 participants in a cross-sectional survey (1996) and a cohort study (1997–2000), respectively, were used for the analysis. Data on the FINDRISC and oral glucose tolerance test parameters were available from each participant. The predictive value of the FINDRISC was cross-sectionally evaluated using the area under the curve-receiver operating characteristics method and by correlation analyses. A validation of the cross-sectional results was performed on the prospective data from the cohort study. Results: The FINDRISC was significantly correlated with markers of insulin resistance. The receiver operating characteristics-area under the curve for the prediction of a homeostasis model assessment insulin resistance index of more than five was 0.78 in the cross-sectional survey and 0.74 at baseline of the cohort study. Moreover, the FINDRISC at baseline was significantly associated with disease evolution (P &lt; 0.01), which was defined as the change of glucose tolerance during the 3 yr follow-up. Conclusions: The results indicate that the FINDRISC can be applied to detect insulin resistance in a population at high risk for type 2 diabetes and predict future impairment of glucose tolerance.

scholarly journals Sustained Decrease of Early-Phase Insulin Secretion in Japanese Women with Gestational Diabetes Mellitus who Developed Impaired Glucose Tolerance and Impaired Fasting Glucose Postpartum

2015 ◽  
Vol 6 ◽  
pp. JCM.S32743 ◽  
Author(s):  
Hiroko Katayama ◽  
Daisuke Tachibana ◽  
Akihiro Hamuro ◽  
Takuya Misugi ◽  
Koka Motoyama ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Plasma Glucose Level ◽  
Fasting Glucose ◽  
Japanese Women ◽  
Insulinogenic Index ◽  
Model Assessment ◽  
Homeostasis Model Assessment

Objective The aim of this study was to compare glucose intolerance in the antenatal and the postpartum periods using a 75-g oral glucose tolerance test (OGTT) in the Japanese women with gestational diabetes mellitus (GDM) using a retrospective design. Patients and Methods Data were obtained from 85 Japanese women with GDM who delivered from April 2011 through April 2015 and who underwent an OGTT 6–14 weeks postpartum. The women were divided into two groups based on the results of the postpartum OGTT: one group with normal glucose tolerance (NGT) and the other with impaired glucose tolerance (IGT) as well as impaired fasting glucose (IFG). We analyzed the associations between postpartum IGT–IFG and various factors. Results Antenatally, a significant difference was observed between the groups only in the 1-hour plasma glucose level of the 75-g OGTT. Postpartum results of plasma glucose level were significantly higher at 0.5, 1, and 2 hours in the IGT–IFG group than those in the NGT group. Moreover, a significant decrease in the levels of 0.5-hour immunoreactive insulin and insulinogenic index was observed in the IGT–IFG group compared to those in the NGT group. Homeostasis model assessment-insulin resistance and homeostasis model assessment β-cell function of both groups were found to significantly decrease in the postpartum period; however, there was no significant change in the insulinogenic index of either group. Conclusions Our study clearly showed that the postpartum IGT and IFG levels of Japanese women with GDM are affected by impaired early-phase insulin secretion; however, insulin resistance promptly improves.

scholarly journals Gender-specific programming of insulin secretion and action

2002 ◽  
Vol 175 (3) ◽  
pp. 757-767 ◽  
Author(s):  
MC Sugden ◽  
MJ Holness
Keyword(s):  
Insulin Resistance ◽  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Early Life ◽  
Insulin Response ◽  
Protein Restriction ◽  
Female Rats ◽  
Male And Female ◽  
Early Protein ◽  
Gender Specific

Insulin secretion and glucose tolerance were studied in 20-week-old male and female offspring of rat dams maintained on an isocaloric 20% or 8% protein diet during pregnancy and lactation after transfer to the same diet at weaning. Protein-restricted male and female offspring were also weaned onto a 20% protein diet. In males, post-absorptive insulin concentrations were suppressed by protein restriction from conception to adulthood (by 41%; P<0.001); however, basal insulin levels were 2.6-fold higher (P<0.001) if protein restriction was limited to gestation and lactation. Post-absorptive insulinaemia in females was unaffected by early or sustained protein restriction, but was lower than for males in the control group and the group exposed to protein restriction during early life alone (by 40% (P<0.001) and 52% (P<0.001) respectively). Plasma insulin/blood glucose ratios were higher in males compared with females in both control and early protein-restricted groups (1.6-fold (P<0.05) and 2.3-fold (P<0.001) respectively). A positive linear relationship existed between mean ambient insulin and glucose concentrations in males (r=1.0) and females (r=0.9), but the gradient was 12.4-fold greater (P<0.01) in males. beta-Cell function was evaluated after intravenous glucose challenge. In males, the acute insulin response and the suprabasal 30-min area under the insulin curve were dramatically higher in rats exposed to protein restriction during gestation and lactation alone (2.6- and 2.8-fold respectively; P<0.001). In contrast, these parameters were lowered by extending the exposure to protein restriction to adulthood in males, and by either early or prolonged exposure to protein restriction in females. The insulin resistance index was increased (2.5-fold; P<0.001) in male, but not female, rats exposed to protein restriction during gestation and lactation alone, and was not increased by extending the period of protein restriction to adulthood in either sex. Thus the data have demonstrated gender-specific lowering of insulin sensitivity due to protein restriction during early life only. The insulinogenic index (insulin response in relation to prevailing glycaemia) was increased in male, but not female, rats exposed to protein restriction during gestation and lactation alone (3.0-fold; P<0.001). A modest decline in insulin secretion in the female groups exposed to protein restriction until either the end of lactation or adulthood was compensated by increased insulin sensitivity, as demonstrated by significant decreases in the insulin resistance index in both groups (by 48% and 52% respectively; P<0.05). Glucose disappearance rates did not differ between the male and female control or early protein-restricted groups but were higher in both male (31%; P<0.05) and female groups (46%; P<0.001) exposed to protein restriction from conception to adulthood. Marked gender differences in glucose-stimulated insulin secretion were not associated with gender differences with respect to glucose tolerance. Our data therefore demonstrated that exposure to protein restriction during early life alone leads to relative insulin resistance and hyperinsulinaemia in adulthood, but this relationship is gender specific, observed only in males, and glucose tolerance is maintained.

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