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 <35 yr) people with normal glucose tolerance (NGT) and old (age >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.

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 Session 7: Early nutrition and later health Early developmental pathways of obesity and diabetes risk

2007 ◽  
Vol 66 (3) ◽  
pp. 451-457 ◽  
Author(s):  
D. B. Dunger ◽  
B. Salgin ◽  
K. K. Ong
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Weight Gain ◽  
Cell Mass ◽  
Disposition Index ◽  
Β Cell ◽  
Igf I ◽  
The Face

Size at birth and patterns of postnatal weight gain have been associated with adult risk for the development of type 2 diabetes in many populations, but the putative pathophysiological link remains unknown. Studies of contemporary populations indicate that rapid infancy weight gain, which may follow fetal growth restriction, is an important risk factor for the development of childhood obesity and insulin resistance. Data from the Avon Longitudinal Study of Pregnancy and Childhood shows that rapid catch-up weight gain can lead to the development of insulin resistance, as early as 1 year of age, in association with increasing accumulation of central abdominal fat mass. In contrast, the disposition index, which reflects the β-cells ability to maintain insulin secretion in the face of increasing insulin resistance, is much more closely related to ponderal index at birth than postnatal catch-up weight gain. Infants with the lowest ponderal index at birth show a reduced disposition index at aged 8 years associated with increases in fasting NEFA levels. The disposition index is also closely related to childhood height gain and insulin-like growth factor-I (IGF-I) levels; reduced insulin secretory capacity being associated with reduced statural growth, and relatively short stature with reduced IGF-I levels at age 8 years. IGF-I may have an important role in the maintenance of β-cell mass, as demonstrated by recent studies of pancreatic β-cell IGF-I receptor knock-out and adult observational studies indicating that low IGF-I levels are predictive of subsequent risk for the development of type 2 diabetes. However, as insulin secretion is an important determinant of IGF-I levels, cause and effect may be difficult to establish. In conclusion, although rapid infancy weight gain and increasing rates of childhood obesity will increase the risk for the development of insulin resistance, prenatal and postnatal determinants of β-cell mass may ultimately be the most important determinants of an individual's ability to maintain insulin secretion in the face of increasing insulin resistance, and thus risk for the development of type 2 diabetes.

Plasma Secretagogin is Increased in Individuals with Glucose Dysregulation

2019 ◽  
Author(s):  
Chao Yang ◽  
Hua Qu ◽  
Xiaolan Zhao ◽  
Yingru Hu ◽  
Jiayao Xiong ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Cell Function ◽  
Model Assessment ◽  
Homeostasis Model Assessment ◽  
Β Cells ◽  
Β Cell ◽  
Β Cell Function ◽  
First Phase Insulin Secretion

Abstract Objective Secretagogin, a Ca2+ binding protein, is one of the most abundant proteins in pancreatic β-cells and is critical for maintaining the structural integrity and signaling competence of β-cells. This study seeks to assess the concentrations of plasma secretagogin in participants with prediabetes (pre-DM) and newly diagnosed type 2 diabetes (T2DM) and to explore its relationship to parameters of glucose and lipid metabolism, first-phase insulin secretion, insulin resistance and pancreatic β-cell function. Materials and Methods A total of 126 eligible subjects were divided into three groups: a normal glucose tolerance (NGT, n=45), a pre-DM (n=30), and a T2DM (n=51) group. An intravenous glucose tolerance test (IVGTT) was performed, and clinical and biochemical parameters were measured for all subjects. Results Plasma secretagogin levels were significantly higher in both pre-DM and T2DM patients compared with NGT subjects and were highest in the T2DM group. Correlation analysis showed that plasma secretagogin levels were positively correlated with fasting plasma glucose, postchallenge plasma glucose (2hPG), HbA1c and body mass index (BMI) but were not correlated with waist-hip ratio, blood pressure, lipid profiles, fasting serum insulin, homeostasis model assessment for insulin resistance, homeostasis model assessment for β-cell function and first-phase insulin secretion indicators. Multiple logistic regression analysis revealed that 2hPG and BMI were independent predictors for elevation of plasma secretagogin concentrations. Conclusions Increased circulating secretagogin might be a molecular predictor for early diagnosis of diabetes. Further studies are needed to confirm this finding and explore the role of secretagogin in obesity.

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 Islet adaptive changes to fructose-induced insulin resistance: β-cell mass, glucokinase, glucose metabolism, and insulin secretion

2008 ◽  
Vol 200 (2) ◽  
pp. 139-149 ◽  
Author(s):  
B Maiztegui ◽  
M I Borelli ◽  
M A Raschia ◽  
H Del Zotto ◽  
J J Gagliardino
Keyword(s):  
Insulin Resistance ◽  
Insulin Secretion ◽  
Glucose Metabolism ◽  
Glucose Tolerance ◽  
Protein Expression ◽  
Impaired Glucose Tolerance ◽  
Insulin Release ◽  
Cell Mass ◽  
Normal Male ◽  
Β Cell

β-Cell mass, hexokinase/glucokinase (HK/GK) activity, glucose metabolism and insulin secretion were studied in the islets of rats with fructose-induced insulin resistance (IR). Normal male Wistar rats were fed a standard commercial diet and water without (control, C) or with 10% fructose-rich diet (FRD) for 3 weeks. Blood glucose (strips), triglyceride (commercial kit), and insulin (RIA) levels were measured at the time of death. Glucose-induced insulin release, glucose metabolism (14CO2 and 3H2O production from d-[U-14C]- and d-[5-3H]-glucose) and HK/GK activity (G-6-P production), transcription (RT-PCR), protein expression (Western blot), and cellular compartmentalization were measured in isolated islets (collagenase digestion). FRD rats presented normoglycemia but impaired glucose tolerance, hypertriglyceridemia, hyperinsulinemia, and increased HOMA-IR index. In these rats, β-cell mass decreased significantly by 33%, with a 44% increase in the percentage of apoptotic cells. Glucose-induced insulin release and islet glucose metabolism were higher in FRD rats. While GK activity (total and cytosolic fraction) and protein expression were significantly higher in FRD islets, HK showed no change in any of these parameters. Our results demonstrate that the changes induced by dietary-induced IR upon β-cell function and mass are strongly conditional on the nutrient model used. In our model (intact animals with impaired glucose tolerance), GK activity increases through mechanisms previously shown only in vitro or under highly hyperglycemic conditions. Such an increase plays a pivotal role in the adaptive increased release of insulin in response to IR, even in the presence of marked β-cell mass reduction.

scholarly journals Arsenic exposure induces glucose intolerance and alters global energy metabolism

2018 ◽  
Vol 314 (2) ◽  
pp. R294-R303 ◽  
Author(s):  
Andrew G. Kirkley ◽  
Christopher M. Carmean ◽  
Daniel Ruiz ◽  
Honggang Ye ◽  
Shane M. Regnier ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Drinking Water ◽  
Insulin Secretion ◽  
Energy Metabolism ◽  
Glucose Tolerance ◽  
Arsenic Exposure ◽  
Β Cell ◽  
Peripheral Insulin Resistance ◽  
The Impact

Environmental pollutants acting as endocrine-disrupting chemicals (EDCs) are recognized as potential contributors to metabolic disease pathogenesis. One such pollutant, arsenic, contaminates the drinking water of ~100 million people globally and has been associated with insulin resistance and diabetes in epidemiological studies. Despite these observations, the precise metabolic derangements induced by arsenic remain incompletely characterized. In the present study, the impact of arsenic on in vivo metabolic physiology was examined in 8-wk-old male C57BL/6J mice exposed to 50 mg/l inorganic arsenite in their drinking water for 8 wk. Glucose metabolism was assessed via in vivo metabolic testing, and feeding behavior was analyzed using indirect calorimetry in metabolic cages. Pancreatic islet composition was assessed via immunofluorescence microscopy. Arsenic-exposed mice exhibited impaired glucose tolerance compared with controls; however, no difference in peripheral insulin resistance was noted between groups. Instead, early insulin release during glucose challenge was attenuated relative to the rise in glycemia. Despite decreased insulin secretion, pancreatic β-cell mass was not altered, suggesting that arsenic primarily disrupts β-cell function. Finally, metabolic cage analyses revealed that arsenic exposure induced novel alterations in the diurnal rhythm of food intake and energy metabolism. Taken together, these data suggest that arsenic exposure impairs glucose tolerance through functional impairments in insulin secretion from β-cells rather than by augmenting peripheral insulin resistance. Further elucidation of the mechanisms underlying arsenic-induced behavioral and β-cell-specific metabolic disruptions will inform future intervention strategies to address this ubiquitous environmental contaminant and novel diabetes risk factor.

Effect of lowering postprandial hyperglycemia on insulin secretion in older people with impaired glucose tolerance

2004 ◽  
Vol 287 (5) ◽  
pp. E906-E911 ◽  
Author(s):  
Annette M. Chang ◽  
Marla J. Smith ◽  
Cathie J. Bloem ◽  
Andrzej T. Galecki ◽  
Jeffrey B. Halter
Keyword(s):  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Older People ◽  
Postprandial Glucose ◽  
Tolerance Test ◽  
Β Cell ◽  
Intravenous Glucose ◽  
Glucose Levels ◽  
Cell Dysfunction ◽  
Chronic Hyperglycemia

Glucose tolerance declines with age, resulting in a high prevalence of diabetes and impaired glucose tolerance (IGT) in the older population. Hyperglycemia per se can lead to impaired β-cell function (glucose toxicity). We tested the role of glucose toxicity in age-related β-cell dysfunction in older people (65 ± 8 yr) with IGT treated with the α-glucosidase inhibitor acarbose ( n = 14) or placebo ( n = 13) for 6 wk in a randomized, double-blind study. Baseline and posttreatment studies included 1) an oral glucose tolerance test (OGTT), 2) 1-h postprandial glucose monitoring, 3) a frequently sampled intravenous glucose tolerance test (insulin sensitivity, or SI), and 4) glucose ramp clamp (insulin secretion rates, or ISR), in which a variable glucose infusion increases plasma glucose from 5 to 10 mM. The treatment groups had similar baseline body mass index; fasting, 2-h OGTT, and 1-h postprandial glucose levels; and SI. In these carefully matched older people with IGT, both fasting (5.7 ± 0.2 vs. 6.3 ± 0.2 mM, P = 0.002) and 1-h postprandial glucose levels (6.9 ± 0.3 vs. 8.2 ± 0.4 mM, P = 0.02) were significantly lower in the acarbose than in the placebo group. Despite this reduction of chronic hyperglycemia in the acarbose vs. placebo group, measures of insulin secretion (ISR area under the curve: 728 ± 55 vs. 835 ± 81 pmol/kg, P = 0.9) and acute insulin response to intravenous glucose (329 ± 67 vs. 301 ± 54 pM, P = 0.4) remained unchanged and impaired. Thus short-term improvement of chronic hyperglycemia does not reverse β-cell dysfunction in older people with IGT.

scholarly journals Evaluating the Effect of Acarbose Treatment on Insulin Secretion and Sensitivity in Early Diabetes Using a Novel Interpretation of the Disposition Index Equation

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Clarissa Hanna ◽  
Tamara Hannon ◽  
Robert V. Considine ◽  
Kieren J. Mather
Keyword(s):  
Insulin Resistance ◽  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Inverse Relationship ◽  
Treatment Effects ◽  
Cell Function ◽  
Disposition Index ◽  
Β Cell ◽  
Progressive Decline ◽  
Analytic Methods

Background and Hypothesis: In pathologic states such as obesity and insulin resistance, there is a progressive decline in insulin sensitivity requiring greater insulin secretion to maintain normoglycemia. The inverse relationship between insulin sensitivity and secretion is mathematically defined by the Disposition Index (DI), a measure of βcell function adjusted for insulin sensitivity. We are working to generalize the DI equation to allow direct physiologic interpretation of the DI term, and of the slope relating insulin secretion with insulin sensitivity. We tested study treatment effects hypotheses using these new analytic methods. Background and Hypothesis: In pathologic states such as obesity and insulin resistance, there is a progressive decline in insulin sensitivity requiring greater insulin secretion to maintain normoglycemia. The inverse relationship between insulin sensitivity and secretion is mathematically defined by the Disposition Index (DI), a measure of βcell function adjusted for insulin sensitivity. We are working to generalize the DI equation to allow direct physiologic interpretation of the DI term, and of the slope relating insulin secretion with insulin sensitivity. We tested study treatment effects hypotheses using these new analytic methods. Results: These analyses revealed statistically significant 1-year changes in DI, in secretion-sensitivity coupling slopes, and in the joint changes in secretion and sensitivity. However, these treatment effects did not differ by randomized treatment group, suggesting an on-study effect beyond the randomized treatments. Conclusion and Potential Impact:  We have applied a novel analytic approach to evaluate the secretion-sensitivity relationship modeled by the disposition index equation to investigate the effect of randomized therapy on β-cell function in a placebo-controlled randomized clinical trial. These analyses revealed study effects on the secretion-sensitivity relationship that have not been previously described, suggesting that this novel approach will have value in clinical studies of β-cell dysfunction and treatment effects.  

scholarly journals Limitation of the Homeostasis Model Assessment to Predict Insulin Resistance and β-Cell Dysfunction in Older People

2006 ◽  
Vol 91 (2) ◽  
pp. 629-634 ◽  
Author(s):  
Annette M. Chang ◽  
Marla J. Smith ◽  
Cathie J. Bloem ◽  
Andrzej T. Galecki ◽  
Jeffrey B. Halter ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Glucose Tolerance ◽  
Older People ◽  
Insulin Response ◽  
Weighted Kappa ◽  
Medical Setting ◽  
Model Assessment ◽  
Homeostasis Model Assessment ◽  
Β Cell ◽  
Age Related

Context: Studies in older people have shown inconsistent agreement between homeostasis model assessment of insulin resistance (HOMA-IR) and dynamic measures of insulin action and have not evaluated HOMA β-cell. Objective: We compared measures of insulin sensitivity and β-cell function from the frequently sampled iv glucose tolerance test (FSIGT) to HOMA models. Design/Patients/Setting/Intervention: Two hundred fourteen young and old with normal glucose tolerance (NGT) and old with impaired glucose tolerance (IGT) participated in a retrospective analysis of FSIGT data in a university medical setting. Main Outcome Measure: Sensitivity to insulin (SI) and acute insulin response to glucose (AIRg) from FSIGT were compared with HOMA models. Results: SI and HOMA-IR measures identified similar patterns of increasing insulin resistance in the two older groups, compared with younger people with NGT, with the greatest degree of insulin resistance in older people with IGT (P &lt; 0.05 vs. young and old NGT for both SI and HOMA-IR). Agreement between HOMA-IR and SI was moderate (weighted kappa = 0.51). AIRg was similar in young and old NGT but was markedly decreased in old IGT (P &lt; 0.05 vs. young and old NGT). HOMA-β-cell was similar in the three groups. Agreement between HOMA β-cell and AIRg was weak (weighted kappa = 0.35). Conclusions: HOMA-IR may detect age-related insulin resistance when comparing large populations of older people. However, dynamic testing appears to be necessary to quantitate diminished insulin secretion in older people.

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