45 results on '"Bergman, Richard N."'
Search Results
2. Rapid development of cardiac dysfunction in a canine model of insulin resistance and moderate obesity
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Broussard, Josiane L., Nelson, Michael D., Kolka, Cathryn M., Bediako, Isaac Asare, Paszkiewicz, Rebecca L., Smith, Laura, Szczepaniak, Edward W., Stefanovski, Darko, Szczepaniak, Lidia S., and Bergman, Richard N.
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- 2016
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3. Elevated nocturnal NEFA are an early signal for hyperinsulinaemic compensation during diet-induced insulin resistance in dogs
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Broussard, Josiane L., Kolka, Cathryn M., Castro, Ana V. B., Asare Bediako, Isaac, Paszkiewicz, Rebecca L., Szczepaniak, Edward W., Szczepaniak, Lidia S., Knutson, Kristen L., Kim, Stella P., and Bergman, Richard N.
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- 2015
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4. Measures of glucose homeostasis during and after duodenal exclusion using a duodenal-jejunal bypass liner in a normoglycemic, nonobese canine model.
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Paszkiewicz, Rebecca L., Burch, Miguel A., Asare Bediako, Isaac, Mkrtchyan, Hasmik, Piccinini, Francesca, Ader, Marilyn, Bresee, Catherine, and Bergman, Richard N.
- Abstract
Discovering the role duodenal exclusion plays in weight loss and resolution of type 2 diabetes (T2D) may help refine the surgical and nonsurgical treatment of obesity and T2D. To assess changes in glucose homeostasis due to duodenal exclusion using a duodenal-jejunal bypass liner (DJBL) in a nonobese canine model. Academic laboratory setting. An intravenous glucose tolerance test (IVGTT), and a mixed-meal tolerance test (MMTT) at baseline, 1, and 6 weeks post DJBL implantation (I1 and I6, respectively), and 1 and 6 weeks post DJBL removal (R1 and R6, respectively) were done in canines (n = 7) fed a normal chow diet. Placement of the DJBL induced weight loss that was maintained until 4 weeks post removal (R4), despite normal food intake. Total bile acids (TBA) and glucagon-like peptide-1 (GLP-1) during the MMTT were significantly increased at I1 and were associated with increased lactate and free fatty acids. Hypoglycemia counter-regulation was blunted during the IVGTT at I1 and I6, returning to baseline at R1. While there were no changes to insulin sensitivity during the experiment, glucose tolerance was significantly increased following the removal of the DJBL at R1. These data show that in a normoglycemic, nonobese canine model, duodenal exclusion induces energy intake-independent weight loss and negative metabolic effects that are reversed following re-exposure of the small intestine to nutrients. • Duodenal-jejunal bypass liner (DJBL) induced food intake-independent weight loss • Bile acids and GLP-1 increased but not insulin sensitivity • Hypoglycemia counterregulation was impaired during duodenal exclusion • Removal of the DJBL improved measures of glucose homeostasis [ABSTRACT FROM AUTHOR]
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- 2022
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5. Hyperinsulinemic Compensation for Insulin Resistance Occurs Independent of Elevated Glycemia in Male Dogs.
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Ader, Marilyn and Bergman, Richard N
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INSULIN resistance ,MAGNETIC resonance imaging ,INSULIN sensitivity ,HYPERINSULINISM ,TYPE 2 diabetes - Abstract
Insulin resistance engenders a compensatory increase in plasma insulin. Inadequate compensation is a primary element in the pathogenesis of type 2 diabetes. The signal that heralds developing insulin resistance and initiates hyperinsulinemic compensation is not known. It has often been assumed to be increased glucose. We tested this assumption by determining whether development of fasting and/or glucose-stimulated hyperinsulinemia with diet-induced insulin resistance occurs because of concomitant elevation of glycemia. Male dogs (n = 58) were fed a hypercaloric, fat-supplemented diet for 6 weeks. Dogs underwent magnetic resonance imaging to quantify total and regional (visceral, subcutaneous) adiposity as well as euglycemic hyperinsulinemic clamps. A subset of animals also underwent an insulin-modified intravenous glucose tolerance test to assess insulin sensitivity, acute insulin response (AIRg), and glucose effectiveness. Fat feeding caused modest weight gain, increased visceral and subcutaneous fat, and insulin resistance at both peripheral and hepatic levels. Hyperinsulinemic compensation was observed in fasting levels as well as increased AIRg. However, we observed absolutely no increase in carefully measured fasting, evening (6 to 8 pm) or nocturnal glycemia (2 to 4 am). Insulin resistance and hyperinsulinemia occurred despite no elevation in 24-hour glucose. Compensatory development of hyperinsulinemia during diet-induced insulin resistance occurs without elevated fasting or 24-hour glycemia. These data refute the idea that glucose itself is a requisite signal for β-cell upregulation. Alternative feedback mechanisms need to be identified. [ABSTRACT FROM AUTHOR]
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- 2021
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6. Origins and History of the Minimal Model of Glucose Regulation.
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Bergman, Richard N.
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INSULIN sensitivity ,INSULIN ,GLUCOSE ,GLUCOSE clamp technique ,FREE fatty acids ,LIPOLYSIS ,GLUCOSE tolerance tests ,TYPE 2 diabetes - Abstract
It has long been hoped that our understanding of the pathogenesis of diabetes would be helped by the use of mathematical modeling. In 1979 Richard Bergman and Claudio Cobelli worked together to find a "minimal model" based upon experimental data from Bergman's laboratory. Model was chosen as the simplest representation based upon physiology known at the time. The model itself is two quasi-linear differential equations; one representing insulin kinetics in plasma, and a second representing the effects of insulin and glucose itself on restoration of the glucose after perturbation by intravenous injection. Model would only be sufficient if it included a delay in insulin action; that is, insulin had to enter a remote compartment, which was interstitial fluid (ISF). Insulin suppressed endogenous glucose output (by liver) slowly. Delay proved to be due to initial suppression of lipolysis; resultant lowering of free fatty acids reduced liver glucose output. Modeling also demanded that normalization of glucose after injection included an effect of glucose itself on glucose disposal and endogenous glucose production – these effects were termed "glucose effectiveness." Insulin sensitivity was calculated from fitting the model to intravenous glucose tolerance test data; the resulting insulin sensitivity index, SI, was validated with the glucose clamp method in human subjects. Model allowed us to examine the relationship between insulin sensitivity and insulin secretion. Relationship was described by a rectangular hyperbola, such that Insulin Secretion x Insulin Sensitivity = Disposition Index (DI). Latter term represents ability of the pancreatic beta-cells to compensate for insulin resistance due to factors such as obesity, pregnancy, or puberty. DI has a genetic basis, and predicts the onset of Type 2 diabetes. An additional factor was clearance of insulin by the liver. Clearance varies significantly among animal or human populations; using the model, clearance was shown to be lower in African Americans than Whites (adults and children), and may be a factor accounting for greater diabetes prevalence in African Americans. The research outlined in the manuscript emphasizes the powerful approach by which hypothesis testing, experimental studies, and mathematical modeling can work together to explain the pathogenesis of metabolic disease. [ABSTRACT FROM AUTHOR]
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- 2021
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7. The Measurement of Insulin Clearance.
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Piccinini, Francesca and Bergman, Richard N.
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INSULIN , *TYPE 2 diabetes , *GLUCOSE metabolism , *ESTIMATION theory , *DIAGNOSIS of endocrine diseases , *LIVER , *BLOOD sugar , *BIOTRANSFORMATION (Metabolism) , *C-peptide , *ANIMALS , *INSULIN resistance - Abstract
Insulin clearance has recently been highlighted as a fundamental aspect of glucose metabolism, as it has been hypothesized that its impairment could be related to an increased risk of developing type 2 diabetes. This review focuses on methods used to calculate insulin clearance: from the early surrogate indices employing C-peptide:insulin molar ratio, to direct measurement methods used in animal models, to modeling-based techniques to estimate the components of insulin clearance (hepatic versus extrahepatic). The methods are explored and interpreted by critically highlighting advantages and limitations. [ABSTRACT FROM AUTHOR]
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- 2020
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8. Novel aspects of the role of the liver in carbohydrate metabolism.
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Bergman, Richard N., Piccinini, Francesca, Kabir, Morvarid, and Ader, Marilyn
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LIPOLYSIS ,CARBOHYDRATE metabolism ,HIGH-fat diet ,TYPE 2 diabetes ,LIVER ,FREE fatty acids ,LACTATES ,REDUCING diets - Abstract
Malfunction of the liver is a central factor in metabolic disease. Glucose production by liver is complex and controlled via indirect mechanisms; insulin regulates adipose tissue lipolysis, and free fatty acids in turn regulate liver glucose output. This latter concept is confirmed by studies in L-Akt-Foxo1 knockout mice. The adipocyte is a likely locus of hepatic insulin resistance. Also, kidneys play a role in regulating glucose production; denervated kidneys abrogate the effect of fat feeding to cause insulin resistance. Glucose itself is an important regulator of liver metabolism ("glucose effectiveness"); after entering liver, glucose is phosphorylated and can be exported as lactate. Using the dynamic glucose/lactate relationship, we have been able to estimate glucose effectiveness in intact animals and human subjects. Families have been identified with a glucokinase regulatory protein defect; modeling demonstrates elevated glucokinase activity. Insulin clearance by liver is highly variable among normal individuals, and is under environmental control: high fat diet reduces clearance by 30%. Liver insulin clearance is significantly lower in African American (AA) adults and children compared to European American participants, accounting for fasting hyperinsulinemia in AA. We hypothesize that reduced hepatic insulin clearance causes peripheral insulin resistance and increased Type 2 diabetes in AA. • Control of glucose production • Hepatic and extrahepatic Insulin clearance • Glucose effectiveness and hepatic glucose uptake • Ethnic differences in insulin clearance • Pathogenesis of Type 2 diabetes [ABSTRACT FROM AUTHOR]
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- 2019
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9. Hypothesis: Role of Reduced Hepatic Insulin Clearance in the Pathogenesis of Type 2 Diabetes.
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Bergman, Richard N., Piccinini, Francesca, Kabir, Morvarid, Kolka, Cathryn M., and Ader, Marilyn
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TYPE 2 diabetes , *AFRICAN American children , *INSULIN , *INSULIN resistance , *AFRICAN Americans - Abstract
There is wide variance among individuals in the fraction of insulin cleared by the liver (20% to 80%). Hepatic insulin clearance is 67% lower in African Americans than European Americans. Clearance is also lower in African American children 7-13 years of age. Lower hepatic insulin clearance will result in peripheral hyperinsulinemia: this exacerbates insulin resistance, which stresses the β-cells, possibly resulting in their ultimate failure and onset of type 2 diabetes. We hypothesize that lower insulin clearance can be a primary cause of type 2 diabetes in at-risk individuals. [ABSTRACT FROM AUTHOR]
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- 2019
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10. Peripheral Mechanisms Mediating the Sustained Antidiabetic Action of FGF1 in the Brain.
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Scarlett, Jarrad M., Kenjiro Muta, Brown, Jenny M., Rojas, Jennifer M., Matsen, Miles E., Acharya, Nikhil K., Secher, Anna, Ingvorsen, Camilla, Jorgensen, Rasmus, Høeg-Jensen, Thomas, Stefanovski, Darko, Bergman, Richard N., Piccinini, Francesca, Kaiyala, Karl J., Masakazu Shiota, Morton, Gregory J., Schwartz, Michael W., Muta, Kenjiro, and Shiota, Masakazu
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PANCREATIC beta cells ,FIBROBLAST growth factors ,TYPE 2 diabetes ,INSULIN resistance ,HYPERGLYCEMIA ,BRAIN ,GROWTH factors ,HYPOGLYCEMIC agents ,ANIMALS ,BLOOD sugar ,DIABETES ,GLUCOSE tolerance tests ,INSULIN ,POLYMERASE chain reaction ,RATS ,TRANSFERASES ,THERAPEUTICS - Abstract
We recently reported that in rodent models of type 2 diabetes (T2D), a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1) induces remission of hyperglycemia that is sustained for weeks. To clarify the peripheral mechanisms underlying this effect, we used the Zucker diabetic fatty fa/fa rat model of T2D, which, like human T2D, is characterized by progressive deterioration of pancreatic β-cell function after hyperglycemia onset. We report that although icv FGF1 injection delays the onset of β-cell dysfunction in these animals, it has no effect on either glucose-induced insulin secretion or insulin sensitivity. These observations suggest that FGF1 acts in the brain to stimulate insulin-independent glucose clearance. On the basis of our finding that icv FGF1 treatment increases hepatic glucokinase gene expression, we considered the possibility that increased hepatic glucose uptake (HGU) contributes to the insulin-independent glucose-lowering effect of icv FGF1. Consistent with this possibility, we report that icv FGF1 injection increases liver glucokinase activity by approximately twofold. We conclude that sustained remission of hyperglycemia induced by the central action of FGF1 involves both preservation of β-cell function and stimulation of HGU through increased hepatic glucokinase activity. [ABSTRACT FROM AUTHOR]
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- 2019
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11. Quantitative path to deep phenotyping: Possible importance of reduced hepatic insulin degradation to type 2 diabetes mellitus pathogenesis.
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Bergman, Richard N., Piccinini, Francesca, Asare Bediako, Isaac, Kabir, Morvarid, Kolka, Cathryn, Polidori, David, and Ader, Marilyn
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PHENOTYPES , *TYPE 2 diabetes , *INSULIN resistance , *INSULIN , *CELL physiology - Abstract
The article discusses the use of deep phenotyping in diabetes and the association between reduced hepatic insulin degradation and type 2 diabetes mellitus (T2DM) pathogenesis. Several factors that determine glucose tolerance are discussed including hepatic insulin clearance, variation in hepatic insulin extraction, and insulin signaling. Particular focus is also given to insulin resistance and β-cell function.
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- 2018
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12. Insulin Access to Skeletal Muscle is Preserved in Obesity Induced by Polyunsaturated Diet.
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Broussard, Josiane L., Bergman, Richard N., Bediako, Isaac Asare, Paszkiewicz, Rebecca L., Iyer, Malini S., and Kolka, Cathryn M.
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OBESITY risk factors ,OBESITY -- Nutritional aspects ,SATURATED fatty acids ,PHYSIOLOGICAL effects of unsaturated fatty acids ,OVERWEIGHT persons ,TYPE 2 diabetes ,PHYSIOLOGY ,ANIMAL experimentation ,BIOLOGICAL models ,DIET ,DOGS ,INSULIN ,OBESITY ,RESEARCH funding ,UNSATURATED fatty acids ,SKELETAL muscle - Abstract
Objective: Diets high in saturated fat induce obesity and insulin resistance and impair insulin access to skeletal muscle, leading to reduced insulin levels at the muscle cell surface available to bind insulin receptors and induce glucose uptake. In contrast, diets supplemented with polyunsaturated fat improve insulin sensitivity (SI) and reduce the risk for type 2 diabetes. It was hypothesized that a diet high in polyunsaturated fat would preserve SI and insulin access to muscle, as compared with a diet high in saturated fat.Methods: After 12 weeks of control, saturated (LARD), or polyunsaturated (salmon oil [SO]) high-fat diet feeding, muscle SI and insulin access to skeletal muscle were measured by using lymph, a surrogate of skeletal muscle interstitial fluid.Results: Both high-fat diets induced similar weight gain, yet only LARD impaired SI. Hyperinsulinemia in the LARD group did not induce an increase in basal interstitial insulin, suggesting reduced insulin access to muscle after LARD, but not after SO.Conclusions: A diet high in polyunsaturated fat does not impair insulin access to muscle interstitium or induce insulin resistance as observed with a saturated fat diet, despite similar weight gain. Future studies should determine whether dietary SO supplementation improves impairments in insulin access to skeletal muscle. [ABSTRACT FROM AUTHOR]- Published
- 2018
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13. Hepatic but Not Extrahepatic Insulin Clearance Is Lower in African American Than in European American Women.
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Piccinini, Francesca, Polidori, David C., Gower, Barbara A., and Bergman, Richard N.
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INSULIN ,AFRICAN American women ,EUROPEAN Americans ,ETHNIC differences ,AFRICAN Americans ,C-peptide ,BLACK people ,BLOOD sugar ,GLUCOSE tolerance tests ,LIVER ,MATHEMATICAL models ,TYPE 2 diabetes ,RESEARCH funding ,WHITE people ,THEORY - Abstract
African Americans (AAs) tend to have higher plasma insulin concentrations than European Americans (EAs); the increased insulin concentrations have been attributed to increased secretion and/or decreased insulin clearance by liver or other tissues. This work characterizes the contributions of hepatic versus extrahepatic insulin degradation related to ethnic differences between AAs and EAs. By using a recently developed mathematical model that uses insulin and C-peptide measurements from the insulin-modified, frequently sampled intravenous glucose tolerance test (FSIGT), we estimated hepatic versus extrahepatic insulin clearance in 29 EA and 18 AA healthy women. During the first 20 min of the FSIGT, plasma insulin was approximately twice as high in AAs as in EAs. In contrast, insulin was similar in AAs and EAs after the 20-25 min intravenous insulin infusion. Hepatic insulin first-pass extraction was two-thirds lower in AAs versus EAs in the overnight-fasted state. In contrast, extrahepatic insulin clearance was not lower in AAs than in EAs. The difference in insulin degradation between AAs and EAs can be attributed totally to liver clearance. The mechanism underlying reduced insulin degradation in AAs remains to be clarified, as does the relative importance of reduced liver clearance to increased risk for type 2 diabetes. [ABSTRACT FROM AUTHOR]
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- 2017
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14. Standardized Mixed-Meal Tolerance and Arginine Stimulation Tests Provide Reproducible and Complementary Measures of β-Cell Function: Results From the Foundation for the National Institutes of Health Biomarkers Consortium Investigative Series.
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Shankar, Sudha S., Vella, Adrian, Raymond, Ralph H., Staten, Myrlene A., Calle, Roberto A., Bergman, Richard N., Cao, Charlie, Chen, Danny, Cobelli, Claudio, Man, Chiara Dalla, Deeg, Mark, Dong, Jennifer Q., Lee, Douglas S., Polidori, David, Robertson, R. Paul, Ruetten, Hartmut, Stefanovski, Darko, Vassileva, Maria T., Weir, Gordon C., and Fryburg, David A.
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GLUCOSE tolerance tests ,INSULIN ,PANCREATIC secretions ,GLUCOSE ,ARGININE ,TYPE 2 diabetes diagnosis ,BLOOD sugar ,INSULIN resistance ,ISLANDS of Langerhans ,TYPE 2 diabetes ,PREDIABETIC state ,RESEARCH evaluation ,RESEARCH funding ,WEIGHTS & measures ,CASE-control method ,DIAGNOSIS - Abstract
Objective: Standardized, reproducible, and feasible quantification of β-cell function (BCF) is necessary for the evaluation of interventions to improve insulin secretion and important for comparison across studies. We therefore characterized the responses to, and reproducibility of, standardized methods of in vivo BCF across different glucose tolerance states.Research Design and Methods: Participants classified as having normal glucose tolerance (NGT; n = 23), prediabetes (PDM; n = 17), and type 2 diabetes mellitus (T2DM; n = 22) underwent two standardized mixed-meal tolerance tests (MMTT) and two standardized arginine stimulation tests (AST) in a test-retest paradigm and one frequently sampled intravenous glucose tolerance test (FSIGT).Results: From the MMTT, insulin secretion in T2DM was >86% lower compared with NGT or PDM (P < 0.001). Insulin sensitivity (Si) decreased from NGT to PDM (∼50%) to T2DM (93% lower [P < 0.001]). In the AST, insulin secretory response to arginine at basal glucose and during hyperglycemia was lower in T2DM compared with NGT and PDM (>58%; all P < 0.001). FSIGT showed decreases in both insulin secretion and Si across populations (P < 0.001), although Si did not differ significantly between PDM and T2DM populations. Reproducibility was generally good for the MMTT, with intraclass correlation coefficients (ICCs) ranging from ∼0.3 to ∼0.8 depending on population and variable. Reproducibility for the AST was very good, with ICC values >0.8 across all variables and populations.Conclusions: Standardized MMTT and AST provide reproducible and complementary measures of BCF with characteristics favorable for longitudinal interventional trials use. [ABSTRACT FROM AUTHOR]- Published
- 2016
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15. Improved Performance of Dynamic Measures of Insulin Response Over Surrogate Indices to Identify Genetic Contributors of Type 2 Diabetes: The GUARDIAN Consortium.
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Palmer, Nicholette D., Wagenknecht, Lynne E., Langefeld, Carl D., Nan Wang, Buchanan, Thomas A., Xiang, Anny H., Allayee, Hooman, Bergman, Richard N., Raffel, Leslie J., Chen, Yii-Der Ida, Haritunians, Talin, Fingerlin, Tasha, Goodarzi, Mark O., Taylor, Kent D., Rotter, Jerome I., Watanabe, Richard M., Bowden, Donald W., and Wang, Nan
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PHYSIOLOGICAL effects of insulin ,TYPE 2 diabetes ,HOMEOSTASIS ,PHYSIOLOGICAL effects of glucose ,PHENOTYPES ,BLOOD sugar ,GLUCOSE tolerance tests ,INSULIN ,INSULIN resistance ,RESEARCH funding - Abstract
Type 2 diabetes (T2D) is a heterogeneous disorder with contributions from peripheral insulin resistance and β-cell dysfunction. For minimization of phenotypic heterogeneity, quantitative intermediate phenotypes characterizing basal glucose homeostasis (insulin resistance and HOMA of insulin resistance [HOMAIR] and of β-cell function [HOMAB]) have shown promise in relatively large samples. We investigated the utility of dynamic measures of glucose homeostasis (insulin sensitivity [SI] and acute insulin response [AIRg]) evaluating T2D-susceptibility variants (n = 57) in Hispanic Americans from the GUARDIAN Consortium (n = 2,560). Basal and dynamic measures were genetically correlated (HOMAB-AIRg: ρG = 0.28-0.73; HOMAIR-SI: ρG = -0.73 to -0.83) with increased heritability for the dynamic measure AIRg Significant association of variants with dynamic measures (P < 8.77 × 10(-4)) was observed. A pattern of superior performance of AIRg was observed for well-established loci including MTNR1B (P = 9.46 × 10(-12)), KCNQ1 (P = 1.35 × 10(-4)), and TCF7L2 (P = 5.10 × 10(-4)) with study-wise statistical significance. Notably, significant association of MTNR1B with AIRg (P < 1.38 × 10(-9)) was observed in a population one-fourteenth the size of the initial discovery cohort. These observations suggest that basal and dynamic measures provide different views and levels of sensitivity to discrete elements of glucose homeostasis. Although more costly to obtain, dynamic measures yield significant results that could be considered physiologically "closer" to causal pathways and provide insight into the discrete mechanisms of action. [ABSTRACT FROM AUTHOR]
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- 2016
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16. Response to Comment on Piccinini and Bergman The Measurement of Insulin Clearance. Diabetes Care 2020;43:2296-2302.
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Bergman, Richard N. and Piccinini, Francesca
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TYPE 2 diabetes , *INSULIN , *DIABETES - Published
- 2021
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17. Sequence data and association statistics from 12,940 type 2 diabetes cases and controls
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Jason, Flannick, Fuchsberger, Christian, Mahajan, Anubha, Teslovich, Tanya M., Agarwala, Vineeta, Gaulton, Kyle J., Caulkins, Lizz, Koesterer, Ryan, Ma, Clement, Moutsianas, Loukas, McCarthy, Davis J., Rivas, Manuel A., Perry, John R. B., Sim, Xueling, Blackwell, Thomas W., Robertson, Neil R., Rayner, N William, Cingolani, Pablo, Locke, Adam E., Tajes, Juan Fernandez, Highland, Heather M., Dupuis, Josee, Chines, Peter S., Lindgren, Cecilia M., Hartl, Christopher, Jackson, Anne U., Chen, Han, Huyghe, Jeroen R., van de Bunt, Martijn, Pearson, Richard D., Kumar, Ashish, Müller-Nurasyid, Martina, Grarup, Niels, Stringham, Heather M., Gamazon, Eric R., Lee, Jaehoon, Chen, Yuhui, Scott, Robert A., Below, Jennifer E., Chen, Peng, Huang, Jinyan, Go, Min Jin, Stitzel, Michael L., Pasko, Dorota, Parker, Stephen C. J., Varga, Tibor V., Green, Todd, Beer, Nicola L., Day-Williams, Aaron G., Ferreira, Teresa, Fingerlin, Tasha, Horikoshi, Momoko, Hu, Cheng, Huh, Iksoo, Ikram, Mohammad Kamran, Kim, Bong-Jo, Kim, Yongkang, Kim, Young Jin, Kwon, Min-Seok, Lee, Juyoung, Lee, Selyeong, Lin, Keng-Han, Maxwell, Taylor J., Nagai, Yoshihiko, Wang, Xu, Welch, Ryan P., Yoon, Joon, Zhang, Weihua, Barzilai, Nir, Voight, Benjamin F., Han, Bok-Ghee, Jenkinson, Christopher P., Kuulasmaa, Teemu, Kuusisto, Johanna, Manning, Alisa, Ng, Maggie C. Y., Palmer, Nicholette D., Balkau, Beverley, Stančáková, Alena, Abboud, Hanna E., Boeing, Heiner, Giedraitis, Vilmantas, Prabhakaran, Dorairaj, Gottesman, Omri, Scott, James, Carey, Jason, Kwan, Phoenix, Grant, George, Smith, Joshua D., Neale, Benjamin M., Purcell, Shaun, Butterworth, Adam S., Howson, Joanna M. M., Lee, Heung Man, Lu, Yingchang, Kwak, Soo-Heon, Zhao, Wei, Danesh, John, Lam, Vincent K. L., Park, Kyong Soo, Saleheen, Danish, So, Wing Yee, Tam, Claudia H. T., Afzal, Uzma, Aguilar, David, Arya, Rector, Aung, Tin, Chan, Edmund, Navarro, Carmen, Cheng, Ching-Yu, Palli, Domenico, Correa, Adolfo, Curran, Joanne E., Rybin, Dennis, Farook, Vidya S., Fowler, Sharon P., Freedman, Barry I., Griswold, Michael, Hale, Daniel Esten, Hicks, Pamela J., Khor, Chiea-Chuen, Kumar, Satish, Lehne, Benjamin, Thuillier, Dorothée, Lim, Wei Yen, Liu, Jianjun, Loh, Marie, Musani, Solomon K., Puppala, Sobha, Scott, William R., Yengo, Loïc, Tan, Sian-Tsung, Taylor, Herman A., Thameem, Farook, Wilson, Gregory, Wong, Tien Yin, Njølstad, Pål Rasmus, Levy, Jonathan C., Mangino, Massimo, Bonnycastle, Lori L., Schwarzmayr, Thomas, Fadista, João, Surdulescu, Gabriela L., Herder, Christian, Groves, Christopher J., Wieland, Thomas, Bork-Jensen, Jette, Brandslund, Ivan, Christensen, Cramer, Koistinen, Heikki A., Doney, Alex S. F., Kinnunen, Leena, Esko, Tõnu, Farmer, Andrew J., Hakaste, Liisa, Hodgkiss, Dylan, Kravic, Jasmina, Lyssenko, Valeri, Hollensted, Mette, Jørgensen, Marit E., Jørgensen, Torben, Ladenvall, Claes, Justesen, Johanne Marie, Käräjämäki, Annemari, Kriebel, Jennifer, Rathmann, Wolfgang, Lannfelt, Lars, Lauritzen, Torsten, Narisu, Narisu, Linneberg, Allan, Melander, Olle, Milani, Lili, Neville, Matt, Orho-Melander, Marju, Qi, Lu, Qi, Qibin, Roden, Michael, Rolandsson, Olov, Swift, Amy, Rosengren, Anders H., Stirrups, Kathleen, Wood, Andrew R., Mihailov, Evelin, Blancher, Christine, Carneiro, Mauricio O., Maguire, Jared, Poplin, Ryan, Shakir, Khalid, Fennell, Timothy, DePristo, Mark, de Angelis, Martin Hrabé, Deloukas, Panos, Gjesing, Anette P., Jun, Goo, Nilsson, Peter, Murphy, Jacquelyn, Onofrio, Robert, Thorand, Barbara, Hansen, Torben, Meisinger, Christa, Hu, Frank B., Isomaa, Bo, Karpe, Fredrik, Liang, Liming, Peters, Annette, Huth, Cornelia, O'Rahilly, Stephen P, Palmer, Colin N. A., Pedersen, Oluf, Rauramaa, Rainer, Tuomilehto, Jaakko, Salomaa, Veikko, Watanabe, Richard M., Syvänen, Ann-Christine, Bergman, Richard N., Bharadwaj, Dwaipayan, Bottinger, Erwin P., Cho, Yoon Shin, Chandak, Giriraj R., Chan, Juliana CN, Chia, Kee Seng, Daly, Mark J., Ebrahim, Shah B., Langenberg, Claudia, Elliott, Paul, Jablonski, Kathleen A., Lehman, Donna M., Jia, Weiping, Ma, Ronald C. W., Pollin, Toni I., Sandhu, Manjinder, Tandon, Nikhil, Froguel, Philippe, Barroso, Inês, Teo, Yik Ying, Zeggini, Eleftheria, Loos, Ruth J. F., Small, Kerrin S., Ried, Janina S., DeFronzo, Ralph A., Grallert, Harald, Glaser, Benjamin, Metspalu, Andres, Wareham, Nicholas J., Walker, Mark, Banks, Eric, Gieger, Christian, Ingelsson, Erik, Im, Hae Kyung, Illig, Thomas, Franks, Paul W., Buck, Gemma, Trakalo, Joseph, Buck, David, Prokopenko, Inga, Mägi, Reedik, Lind, Lars, Farjoun, Yossi, Owen, Katharine R., Gloyn, Anna L., Strauch, Konstantin, Tuomi, Tiinamaija, Kooner, Jaspal Singh, Lee, Jong-Young, Park, Taesung, Donnelly, Peter, Morris, Andrew D., Hattersley, Andrew T., Bowden, Donald W., Collins, Francis S., Atzmon, Gil, Chambers, John C., Spector, Timothy D., Laakso, Markku, Strom, Tim M., Bell, Graeme I., Blangero, John, Duggirala, Ravindranath, Tai, E. Shyong, McVean, Gilean, Hanis, Craig L., Wilson, James G., Seielstad, Mark, Frayling, Timothy M., Meigs, James B., Cox, Nancy J., Sladek, Rob, Lander, Eric S., Gabriel, Stacey, Mohlke, Karen L., Meitinger, Thomas, Groop, Leif, Abecasis, Goncalo, Scott, Laura J., Morris, Andrew P., Kang, Hyun Min, Altshuler, David, Burtt, Noël P., Florez, Jose C., Boehnke, Michael, and McCarthy, Mark I.
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DNA sequencing ,Type 2 diabetes ,Genome-wide association studies - Abstract
To investigate the genetic basis of type 2 diabetes (T2D) to high resolution, the GoT2D and T2D-GENES consortia catalogued variation from whole-genome sequencing of 2,657 European individuals and exome sequencing of 12,940 individuals of multiple ancestries. Over 27M SNPs, indels, and structural variants were identified, including 99% of low-frequency (minor allele frequency [MAF] 0.1–5%) non-coding variants in the whole-genome sequenced individuals and 99.7% of low-frequency coding variants in the whole-exome sequenced individuals. Each variant was tested for association with T2D in the sequenced individuals, and, to increase power, most were tested in larger numbers of individuals (>80% of low-frequency coding variants in ~82 K Europeans via the exome chip, and ~90% of low-frequency non-coding variants in ~44 K Europeans via genotype imputation). The variants, genotypes, and association statistics from these analyses provide the largest reference to date of human genetic information relevant to T2D, for use in activities such as T2D-focused genotype imputation, functional characterization of variants or genes, and other novel analyses to detect associations between sequence variation and T2D.
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- 2017
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18. The Physiology of Insulin Clearance.
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Bergman, Richard N., Kabir, Morvarid, and Ader, Marilyn
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INSULIN , *TYPE 2 diabetes , *NATURE & nurture , *HISPANIC Americans , *DISEASE risk factors - Abstract
In the 1950's, Dr. I. Arthur Mirsky first recognized the possible importance of insulin degradation changes to the pathogenesis of type 2 diabetes. While this mechanism was ignored for decades, insulin degradation is now being recognized as a possible factor in diabetes risk. After Mirsky, the relative importance of defects in insulin release and insulin resistance were recognized as risk factors. The hyperbolic relationship between secretion and sensitivity was introduced, as was the relationship between them, as expressed as the disposition index (DI). The DI was shown to be affected by environmental and genetic factors, and it was shown to be differentiated among ethnic groups. However, the importance of differences in insulin degradation (clearance) on the disposition index relationship remains to be clarified. Direct measure of insulin clearance revealed it to be highly variable among even normal individuals, and to be affected by fat feeding and other physiologic factors. Insulin clearance is relatively lower in ethnic groups at high risk for diabetes such as African Americans and Hispanic Americans, compared to European Americans. These differences exist even for young children. Two possible mechanisms have been proposed for the importance of insulin clearance for diabetes risk: in one concept, insulin resistance per se leads to reduced clearance and diabetes risk. In a second and new concept, reduced degradation is a primary factor leading to diabetes risk, such that lower clearance (resulting from genetics or environment) leads to systemic hyperinsulinemia, insulin resistance, and beta-cell stress. Recent data by Chang and colleagues appear to support this latter hypothesis in Native Americans. The importance of insulin clearance as a risk factor for metabolic disease is becoming recognized and may be treatable. [ABSTRACT FROM AUTHOR]
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- 2022
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19. Mendelian Randomization Studies Do Not Support a Causal Role for Reduced Circulating Adiponectin Levels in Insulin Resistance and Type 2 Diabetes.
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Yaghootkar, Hanieh, Lamina, Claudia, Scott, Robert A., Dastani, Zari, Hivert, Marie-France, Warren, Liling L., Stancáková, Alena, Buxbaum, Sarah G., Lyytikäinen, Leo-Pekka, Henneman, Peter, Ying Wu, Cheung, Chloe Y. Y., Pankow, James S., Jackson, Anne U., Gustafsson, Stefan, Jing Hua Zhao, Ballantyne, Christie M., Weijia Xie, Bergman, Richard N., and Boehnke, Michael
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ADIPONECTIN ,INSULIN resistance ,TYPE 2 diabetes ,INSULIN research ,DIABETES - Abstract
Adiponectin is strongly inversely associated with insulin resistance and type 2 diabetes, but its causal role remains controversial. We used a Mendelian randomization approach to test the hypothesis that adiponectin causally influences insulin resistance and type 2 diabetes. We used genetic variants at the ADIPOQ gene as instruments to calculate a regression slope between adiponectin levels and metabolic traits (up to 31,000 individuals) and a combination of instrumental variables and summary statistics--based genetic risk scores to test the associations with gold-standard measures of insulin sensitivity (2,969 individuals) and type 2 diabetes (15,960 case subjects and 64,731 control subjects). In conventional regression analyses, a 1-SD decrease in adiponectin levels was correlated with a 0.31-SD (95% CI 0.26-0.35) increase in fasting insulin, a 0.34-SD (0.30-0.38) decrease in insulin sensitivity, and a type 2 diabetes odds ratio (OR) of 1.75 (1.47-2.13). The instrumental variable analysis revealed no evidence of a causal association between genetically lower circulating adiponectin and higher fasting insulin (0.02 SD; 95% CI 20.07 to 0.11; N = 29,771), nominal evidence of a causal relationship with lower insulin sensitivity (-0.20 SD; 95% CI -0.38 to -0.02; N = 1,860), and no evidence of a relationship with type 2 diabetes (OR 0.94; 95% CI 0.75-1.19; N = 2,777 case subjects and 13,011 control subjects). Using the ADIPOQ summary statistics genetic risk scores, we found no evidence of an association between adiponectin-lowering alleles and insulin sensitivity (effect per weighted adiponectin-lowering allele: -0.03 SD; 95% CI -0.07 to 0.01; N = 2,969) or type 2 diabetes (OR per weighted adiponectin-lowering allele: 0.99; 95% CI 0.95-1.04; 15,960 case subjects vs. 64,731 control subjects). These results do not provide any consistent evidence that interventions aimed at increasing adiponectin levels will improve insulin sensitivity or risk of type 2 diabetes. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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20. Insulin Clearance and the Incidence of Type 2 Diabetes in Hispanics and African Americans.
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LEE, C. CHRISTINE, HAFFNER, STEVEN M., WAGENKNECHT, LYNNE E., LORENZO, CARLOS, NORRIS, JILL M., BERGMAN, RICHARD N., STEFANOVSKI, DARKO, ANDERSON, ANDREA M., ROTTER, JEROME I., GOODARZI, MARK O., and HANLEY, ANTHONY J.
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TYPE 2 diabetes ,INSULIN therapy ,DISEASE incidence ,HISPANIC Americans ,AFRICAN Americans - Abstract
OBJECTIVE--We aimed to identify factors that are independently associated with the metabolic clearance rate of insulin (MCRI) and to examine the association of MCRI with incident type 2 diabetes in nondiabetic Hispanics and African Americans. RESEARCH DESIGN AND METHODS--We investigated 1,116 participants in the Insulin Resistance Atherosclerosis Study (IRAS) Family Study with baseline examinations from 2000 to 2002 and follow-up examinations from 2005 to 2006. Insulin sensitivity (SI), acute insulin response (AIR), and MCRI were determined at baseline from frequently sampled intravenous glucose tolerance tests. MCRI was calculated as the ratio of the insulin dose over the incremental area under the curve of insulin. Incident diabetes was defined as fasting glucose ≥126 mg/dL or antidiabetic medication use by self-report. RESULTS--We observed that SI and HDL cholesterol were independent positive correlates of MCRI, whereas fasting insulin, fasting glucose, subcutaneous adipose tissue, visceral adipose tissue, and AIR were independent negative correlates (all P < 0.05) at baseline. After 5 years of follow-up, 71 (6.4%) participants developed type 2 diabetes. Lower MCRI was associated with a higher risk of incident diabetes after adjusting for demographics, lifestyle factors, HDL cholesterol, indexes of obesity and adiposity, and insulin secretion (odds ratio 2.01 [95% CI 1.30-3.10], P = 0.0064, per one-SD decrease in loge-transformed MCRI). CONCLUSIONS--Our data showed that lower MCRI predicts the incidence of type 2 diabetes. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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21. Performance of a multi-marker Diabetes Risk Score in the Insulin Resistance Atherosclerosis Study (IRAS), a multi-ethnic US cohort.
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Rowe, Michael W., Bergman, Richard N., Wagenknecht, Lynne E., and Kolberg, Janice A.
- Abstract
Background This study compares a previously developed Diabetes Risk Score to commonly used clinical tools for type 2 diabetes risk evaluation in the Insulin Resistance Atherosclerosis Study (IRAS) cohort, a multi-ethnic US cohort. Available as a clinical test, the PreDx® Diabetes Risk Score uses fasting concentrations of adiponectin, C-reactive protein, ferritin, interleukin-2 receptor alpha, HbA
1c , glucose and insulin, plus age and gender to predict 5-year risk of diabetes. It was developed in a Northern European population. Methods The Diabetes Risk Score was measured using archived fasting plasma specimens from 722 non-diabetic IRAS participants, 17.6% of whom developed diabetes during 5.2 years median follow-up (inter-quartile range: 5.1-5.4 years). The study included non-Hispanic whites (41.8%), Hispanics (34.5%) and African Americans (23.7%). Performance of the algorithm was evaluated by area under the receiver operating characteristic curve (AROC) and risk reclassification against other tools. Results The Diabetes Risk Score discriminates participants who developed diabetes from those who did not significantly better than fasting glucose (AROC = 0.763 versus 0.710, p = 0.003). The Diabetes Risk Score performed equally well in subpopulations defined by race/ethnicity or gender. The Diabetes Risk Score provided a significant net reclassification improvement of 0.24 ( p = 0.01) when comparing predefined low/moderate/high Diabetes Risk Score categories to metabolic syndrome risk factor counting. The Diabetes Risk Score complemented the use of the oral glucose tolerance test by identifying high risk patients with impaired fasting glucose but normal glucose tolerance, 33% of whom converted. Conclusions Measuring the Diabetes Risk Score of elevated-risk US patients could help physicians decide which patients warrant more intensive intervention. The Diabetes Risk Score performed equally well across the ethnic subpopulations present in this cohort. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]- Published
- 2012
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22. Stratifying Type 2 Diabetes Cases by BMI Identifies Genetic Risk Variants in LAMA1 and Enrichment for Risk Variants in Lean Compared to Obese Cases.
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Perry, John R. B., Voight, Benjamin F., Yengo, Loïc, Amin, Najaf, Dupuis, Josée, Ganser, Martha, Grallert, Harald, Navarro, Pau, Man Li, Lu Qi, Steinthorsdottir, Valgerdur, Scott, Robert A., Almgren, Peter, Arking, Dan E., Aulchenko, Yurii, Balkau, Beverley, Benediktsson, Rafn, Bergman, Richard N., Boerwinkle, Eric, and Bonnycastle, Lori
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TYPE 2 diabetes ,DIABETES ,OBESITY ,BODY mass index ,GENOMES - Abstract
Common diseases such as type 2 diabetes are phenotypically heterogeneous. Obesity is a major risk factor for type 2 diabetes, but patients vary appreciably in body mass index. We hypothesized that the genetic predisposition to the disease may be different in lean (BMI<25 Kg/m²) compared to obese cases (BMI≥30 Kg/m²). We performed two case-control genome-wide studies using two accepted cut-offs for defining individuals as overweight or obese. We used 2,112 lean type 2 diabetes cases (BMI<25 kg/m²) or 4,123 obese cases (BMI≥30 kg/m²), and 54,412 unstratified controls. Replication was performed in 2,881 lean cases or 8,702 obese cases, and 18,957 un-stratified controls. To assess the effects of known signals, we tested the individual and combined effects of SNPs representing 36 type 2 diabetes loci. After combining data from discovery and replication datasets, we identified two signals not previously reported in Europeans. A variant (rs8090011) in the LAMA1 gene was associated with type 2 diabetes in lean cases (P = 8.4x10
-9 , OR = 1.13 [95% CI 1.09--1.18]), and this association was stronger than that in obese cases (P = 0.04, OR = 1.03 [95% CI 1.00--1.06]). A variant in HMG20A--previously identified in South Asians but not Europeans--was associated with type 2 diabetes in obese cases (P = 1.3x10-8 , OR = 1.11 [95% CI 1.07-1.15]), although this association was not significantly stronger than that in lean cases (P = 0.02, OR = 1.09 [95% CI 1.02-1.17]). For 36 known type 2 diabetes loci, 29 had a larger odds ratio in the lean compared to obese (binomial P = 0.0002). In the lean analysis, we observed a weighted per-risk allele OR = 1.13 [95% CI 1.10--1.17], P = 3.2x10-14 . This was larger than the same model fitted in the obese analysis where the OR = 1.06 [95% CI 1.05--1.08], P = 2.2x10-16 . This study provides evidence that stratification of type 2 diabetes cases by BMI may help identify additional risk variants and that lean cases may have a stronger genetic predisposition to type 2 diabetes. [ABSTRACT FROM AUTHOR]- Published
- 2012
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23. Disposition Index, Glucose Effectiveness, and Conversion to Type 2 Diabetes.
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LORENZO, CARLOS, WAGENKNECHT, LYNNE E., REWERS, MARIAN J., KARTER, ANDREW J., BERGMAN, RICHARD N., HANLEY, ANTHONY J. G., and HAFFNER, STEVEN M.
- Subjects
GLUCOSE ,TYPE 2 diabetes ,DRUG efficacy ,EPIDEMIOLOGY ,DIABETES risk factors - Abstract
OBJECTIVE- Disposition index (DI) and glucose effectiveness (S[sub G]) are risk factors for diabetes. However, the effect of DI and S[sub G] on future diabetes has not been examined in large epidemiological studies using direct measures. RESEARCH DESIGN AND METHODS-- Insulin sensitivity index (S[sub I]), acute insulin response (AIR), and S[sub G] were measured in 826 participants (aged 40-69 years) in the Insulin Resistance Atherosclerosis Study (IRAS) by the frequently sampled intravenous glucose tolerance test. DI was expressed as S[sub I] x AIR. At the 5-year follow-up examination, 128 individuals (15.5%) had developed diabetes. RESULTS -- The area under the receiver operating characteristic curve of a model with S[sub I] and AIR was similar to that of DI (0.767 vs. 0.774, P = 0.543). In a multivariate logistic regression model that included both DI and S[sub G], conversion to diabetes was predicted by both S[sub G] (odds ratio x 1 SD, 0.61 [0.47-0.80]) and DI (0.68 [0.54-0.85]) after adjusting for demographic variables, fasting and 2-h glucose concentrations, family history of diabetes, and measures of obesity. Age, sex, race/ethnicity, glucose tolerance status, obesity, and family history of diabetes did not have a significant modifying impact on the relation of S[sub G] and DI to incident diabetes. CONCLUSIONS -- The predictive power of DI is comparable to that of its components, S1 and AIR. S[sub G] and DI independently predict conversion to diabetes similarly across race/ethnic groups, varying states of glucose tolerance, family history of diabetes, and obesity. [ABSTRACT FROM AUTHOR]
- Published
- 2010
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24. Detailed Physiologic Characterization Reveals Diverse Mechanisms for Novel Genetic Loci Regulating Glucose and Insulin Metabolism in Humans.
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Ingelsson, Erik, Langenberg, Claudia, Hivert, Marie-France, Prokopenko, Inga, Lyssenko, Valeriya, Dupuis, Josée, Mägi, Reedik, Sharp, Stephen, Jackson, Anne U., Assimes, Themistocles L., Shrader, Peter, Knowles, Joshua W., Zethelius, Björn, Abbasi, Fahim A., Bergman, Richard N., Bergmann, Antje, Berne, Christian, Boehnke, Michael, Bonnycastle, Lori L., and Bornstein, Stefan R.
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INSULIN ,GLUCOSE ,TYPE 2 diabetes ,DIABETIC acidosis ,MONOSACCHARIDES ,HYPOGLYCEMIC agents ,DIABETES - Abstract
OBJECTIVE--Recent genome-wide association studies have revealed loci associated with glucose and insulin-related traits. We aimed to characterize 19 such loci using detailed measures of insulin processing, secretion, and sensitivity to help elucidate their role in regulation of glucose control, insulin secretion and/or action. RESEARCH DESIGN AND METHODS--We investigated associations of loci identified by the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) with circulating pro-insulin, measures of insulin secretion and sensitivity from oral glucose tolerance tests (OGTTs), euglycemic clamps, insulin suppression tests, or frequently sampled intravenous glucose tolerance tests in nondiabetic humans (n = 29,084). RESULTS--The glucose-raising allele in MADD was associated with abnormal insulin processing (a dramatic effect on higher proinsulin levels, but no association with insulinogenic index) at extremely persuasive levels of statistical significance (P = 2.1 x 10
-71 ). Defects in insulin processing and insulin secretion were seen in glucose-raising allele carriers at TCF7L2, SCL30A8, GIPR, and C2CD4B. Abnormalities in early insulin secretion were suggested in glucose-raising allele carriers at MTNR1B, GCK, FADS1, DGKB, and PROX1 (lower insulinogenic index; no association with proinsulin or insulin sensitivity). Two loci previously associated with fasting insulin (GCKR and IGF1) were associated with OGTT-derived insulin sensitivity indices in a consistent direction. CONCLUSIONS--Genetic loci identified through their effect on hyperglycemia and/or hyperinsulinemia demonstrate considerable heterogeneity in associations with measures of insulin processing, secretion, and sensitivity. Our findings emphasize the importance of detailed physiological characterization of such loci for improved understanding of pathways associated with alterations in glucose homeostasis and eventually type 2 diabetes. Diabetes 59:1266-1275, 2010 [ABSTRACT FROM AUTHOR]- Published
- 2010
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25. Insulin enhances glucose-stimulated insulin secretion in healthy humans.
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Bouche, Clara, Lopez, Ximena, Fleischman, Amy, Cypess, Aaron M., O'Shea, Sheila, Stefanovski, Darko, Bergman, Richard N., Rogatsky, Eduard, Stein, Daniel T., Kahn, C. Ronald, Kulkarni, Rohit N., and Goldfine, Allison B.
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INSULIN therapy ,GLUCOSE synthesis ,PANCREATIC beta cells ,C-peptide ,TYPE 2 diabetes ,INSULIN resistance - Abstract
Islet β-cells express both insulin receptors and insulin-signaling proteins. Recent evidence from rodents in vivo and from islets isolated from rodents or humans suggests that the insulin signaling pathway is physiologically important for glucose sensing. We evaluated whether insulin regulates β-cell function in healthy humans in vivo. Glucose-induced insulin secretion was assessed in healthy humans following 4-h saline (low insulin/sham clamp) or isoglycemic-hyperinsulinemic (high insulin) clamps using B28- Asp insulin that could be immunologically distinguished from endogenous insulin. Insulin and C-peptide clearance were evaluated to understand the impact of hyperinsulinemia on estimates of β-cell function. Preexposure to exogenous insulin increased the endogenous insulin secretory response to glucose by ≈40%. C-peptide response also increased, although not to the level predicted by insulin. Insulin clearance was not saturated at hyperin- sulinemia, but metabolic clearance of C-peptide, assessed by infusion of stable isotope-labeled C-peptide, increased modestly during hyperinsulinemic clamp. These studies demonstrate that insulin potentiates glucose-stimulated insulin secretion in vivo in healthy humans. In addition, hyperinsulinemia increases C-peptide clearance, which may lead to modest underestimation of β-cell secretory response when using these methods during prolonged dynamic testing. [ABSTRACT FROM AUTHOR]
- Published
- 2010
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26. Exenatide can reduce glucose independent of islet hormones or gastric emptying.
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Ionut, Viorica, Dan Zheng, Stefanovski, Darko, and Bergman, Richard N.
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GLUCAGON ,TYPE 2 diabetes ,HORMONES ,GLUCOSE ,BLOOD sugar - Abstract
Exenatide is a long-acting glucagon-like peptide-1 (GLP-1) mimetic used in the treatment of type 2 diabetes. There is increasing evidence that GLP-1 can influence glycemia not only via pancreatic (insulinotropic and glucagon suppression) and gastric-emptying effects, but also via an independent mechanism mediated by portal vein receptors. The aim of our study was to investigate whether exenatide has an islet- and gastric-independent glycemia-reducing effect, similar to GLP-1. First, we administered mixed meals, with or without exenatide (20 µg sc) to dogs. Second, to determine whether exenatide-induced reduction in glycemia is independent of slower gastric emptying, in the same animals we infused glucose intraportally (to simulate meal test glucose appearance) with exenatide, exenatide + the intraportal GLP-1 receptor antagonist exendin-(9-39), or saline. Exenatide markedly decreased postprandial glucose: net 0- to 135-min area under the curve = +526 ± 315 and -536 ± 197 mg·dl
-1 ·min-1 with saline and exenatide, respectively (P < 0.05). Importantly, the decrease in plasma glucose occurred without a corresponding increase in post-prandial insulin but was accompanied by delayed gastric emptying and lower glucagon. Significantly lower glycemia was induced by intraportal glucose infusion with exenatide than with saline (92 ± 1 vs. 97 ± 1 mg/dl, P < 0.001) in the absence of hyperinsulinemia or glucagon suppression. The exenatide-induced lower glycemia was partly reversed by intraportal exendin-(9-39): 95 ± 3 and 92 ± 3 mg/dl with exenatide + antagonist and exenatide, respectively (P < 0.01). Our results suggest that, similar to GLP-1, exenatide lowers glycemia via a novel mechanism independent of islet hormones and slowing of gastric emptying. We hypothesize that receptors in the portal vein, via a neural mechanism, increase glucose clearance independent of islet hormones. [ABSTRACT FROM AUTHOR]- Published
- 2008
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27. Quantitative Trait Analysis of Type 2 Diabetes Susceptibility Loci Identified From Whole Genome Association Studies in the Insulin Resistance Atherosclerosis Family Study.
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Palmer, Nicholette D., Goodarzi, Mark O., Langefeld, Carl D., Ziegler, Julie, Norris, Jill M., Haffner, Steven M., Bryer-Ash, Michael, Bergman, Richard N., Wagenknecht, Lynne E., Taylor, Kent D., Rotter, Jerome I., and Bowden, Donald W.
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QUANTITATIVE research ,TYPE 2 diabetes ,GENOMES ,INSULIN resistance ,ATHEROSCLEROSIS - Abstract
OBJECTIVE--Evaluate type 2 diabetes susceptibility variants identified from genome-wide association studies in Hispanic Americans and African Americans from the Insulin Resistance Atherosclerosis Family Study (IRAS-FS) for association with quantitative measures of glucose homeostasis and determine their biological role in vivo. RESEARCH DESIGN AND METHODS--Seventeen type 2 diabetes-associated single nucleotide polymorphisms (SNPs) were genotyped in 1,268 Hispanic- and 581 African-American participants from the IRAS-FS. SNPs were tested for association with quantitative measures of glucose homeostasis, including insulin sensitivity index (S[sub I]), acute insulin response (AIR), and disposition index. RESULTS--Previously identified risk variants in cyclin-dependent kinase 5 regulatory subunit associated protein 1-like 1 (CDKAL1) were associated with reduced AIR (P < 0.0046) in Hispanic Americans. Additionally in Hispanic Americans, the variant in a hypothetical gene (chromosome 11; LOC387761) was significantly associated with AIR (P = 0.0046) with the risk allele showing protective effects, i.e., increased AIR. In both Hispanic- and African-American populations, risk variants at the solute carrier family 30, member 8 (SLC30A8) locus were nominally associated with decreased disposition index (P < 0.078). Risk variants in the insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) locus were associated with a decreased disposition index (P = 0.011) exclusively in Hispanic Americans. CONCLUSIONS--These data indicate a distinct, limited number of diabetes-related genes, more specifically the SNPs in the genes identified in European-derived populations, with modest evidence for association with glucose homeostasis traits in Hispanic Americans and African Americans. We observe evidence that diabetes risk for CDKAL1, SLC30A8, IGF2BP2, and LOC387761 is specifically mediated through defects in insulin secretion. The mechanisms of other predisposing genes remain to be elucidated. [ABSTRACT FROM AUTHOR]
- Published
- 2008
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28. Orchestration of Glucose Homeostasis.
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Bergman, Richard N.
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TYPE 2 diabetes , *DIABETES , *DIAGNOSIS of diabetes , *CARBOHYDRATE intolerance , *COMPUTER systems , *PREVENTION ,DEVELOPING countries ,WESTERN countries - Abstract
The article presents the different approaches in order to address the increasing rates of type 2 diabetes in the U.S., in westernized countries, and in the third world. Understanding the pathogenesis of diabetes would lead to better approaches to diagnose, prevent and to treat existing cases. In the reductionist approach, knowledge of disease would result from describing events at increasingly more microscopic levels. In the systems approach, mathematical or computer models are used.
- Published
- 2007
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29. Subsets of Finns with High HDL to Total Cholesterol Ratio Show Evidence for Linkage to Type 2 Diabetes on Chromosome 6q.
- Author
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Shtir, Corina, Nagakawa, I. Sharon, Duren, William L., Conneely, Karen N., Scott, Laura J., Silander, Kaisa, Valle, Timo T., Tuomilehto, Jaakko, Buchanan, Thomas A., Bergman, Richard N., Collins, Francis S., Boehnke, Michael, and Watanabe, Richard M.
- Abstract
Objectives: The purpose of this study was to examine carefully heterogeneity underlying evidence for linkage to type 2 diabetes (T2DM) on chromosome 6q from two sets of FUSION families. Methods: Ordered subsets analysis (OSA) was performed on two sets of FUSION families. For OSA results showing significant improvement in evidence for linkage, T2DM-related phenotypes were compared between individuals with T2DM within the subset versus the complement. Results: OSA analysis revealed 105 families with the highest average HDL to total cholesterol ratio (HDL ratio) that had strongly increased evidence for linkage (MLS = 7.91 at 78.0 cM; uncorrected p = 0.00002). Subjects with T2DM within this subset were significantly leaner, had lower fasting glucose, insulin, and C-peptide, and more favorable cardiovascular risk profile compared to the complement set of subjects with T2DM. OSA also revealed 33 families with the lowest average fasting insulin that had increased evidence for linkage at a second locus (MLS = 3.45 at 128 cM; uncorrected p = 0.017) coincident with quantitative trait locus linkage analysis results for fasting and 2-hour insulin in subjects without T2DM. Conclusions: These results suggest two diabetes susceptibility loci on chromosome 6q that may affect subsets of individuals with a milder form of T2DM. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]
- Published
- 2007
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30. Association of Transcription Factor 7-Like 2 (TCF7L2) Variants With Type 2 Diabetes in a Finnish Sample.
- Author
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Scott, Laura J., Bonnycastle, Lori L., Willer, Cristen J., Sprau, Andrew G., Jackson, Anne U., Narisu, Narisu, Duren, William L., Chines, Peter S., Stringham, Heather M., Erdos, Michael R., Valle, Timo T., Tuomilehto, Jaakko, Bergman, Richard N., Mohlke, Karen L., Collins, Francis S., and Boehnke, Michael
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TYPE 2 diabetes ,DIABETES ,GENETICS ,ENDOCRINE diseases ,TRANSCRIPTION factors - Abstract
Transcription factor 7-like 2 (TCF7L2) is part of the Wnt signaling pathway. Genetic variants within TCF7L2 on chromosome 10q were recently reported to be associated with type 2 diabetes in Icelandic, Danish, and American (U.S.) samples. We previously observed a modest logarithm of odds score of 0.61 on chromosome 10q, ∼1 Mb from TCF7L2, in the Finland-United States Investigation of NIDDM Genetics study. We tested the five associated TCF7L2 single nucleotide polymorphism (SNP) variants in a Finnish sample of 1,151 type 2 diabetic patients and 953 control subjects. We confirmed the association with the same risk allele (P value <0.05) for all five SNPs. Our strongest results were for rs12255372 (odds ratio [OR] 1.36 [95% CI 1.15-1.61], P = 0.00026) and rs7903146 (1.33 [1.14-1.56], P = 0.00042). Based on the CEU HapMap data, we selected and tested 12 additional SNPs to tag SNPs in linkage disequilibrium with rs12255372. None of these SNPs showed stronger evidence of association than rs12255372 or rs7903146 (OR ≤1.26, P ≥ 0.0054). Our results strengthen the evidence that one or more variants in TCF7L2 are associated with increased risk of type 2 diabetes. Diabetes 55:2649-2653, 2006 [ABSTRACT FROM AUTHOR]
- Published
- 2006
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31. Mitochondrial polymorphisms and susceptibility to type 2 diabetes-related traits in Finns.
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Mohlke, Karen L., Jackson, Anne U., Scott, Laura J., Peck, Erin C., Suh, Yong D., Chines, Peter S., Watanabe, Richard M., Buchanan, Thomas A., Conneely, Karen N., Erdos, Michael R., Narisu, Narisu, Enloe, Sareena, Valle, Timo T., Tuomilehto, Jaakko, Bergman, Richard N., Boehnke, Michael, and Collins, Francis S.
- Subjects
TYPE 2 diabetes ,DISEASE susceptibility ,ADENOSINE triphosphate ,GLUCOSE ,GENETIC polymorphisms - Abstract
Mitochondria play an integral role in ATP production in cells and are involved in glucose metabolism and insulin secretion, suggesting that variants in the mitochondrial genome may contribute to diabetes susceptibility. In a study of Finnish families ascertained for type 2 diabetes mellitus (T2DM), we genotyped single nucleotide polymorphisms (SNPs) based on phylogenetic networks. These SNPs defined eight major haplogroups and subdivided groups H and U, which are common in Finns. We evaluated association with both diabetes disease status and up to 14 diabetes-related traits for 762 cases, 402 non-diabetic controls, and 465 offspring of genotyped females. Haplogroup J showed a trend toward association with T2DM affected status (OR 1.69, P=0.056) that became slightly more significant after excluding cases with affected fathers (OR 1.77, P=0.045). We also genotyped non-haplogroup-tagging SNPs previously reported to show evidence for association with diabetes or related traits. Our data support previous evidence for association of T16189C with reduced ponderal index at birth and also show evidence for association with reduced birthweight but not with diabetes status. Given the multiple tests performed and the significance levels obtained, this study suggests that mitochondrial genome variants may play at most a modest role in glucose metabolism in the Finnish population. Furthermore, our data do not support a reported maternal inheritance pattern of T2DM but instead show a strong effect of recall bias. [ABSTRACT FROM AUTHOR]
- Published
- 2005
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32. Genetic variation near the hepatocyte nuclear factor-4 alpha gene predicts susceptibility to type 2 diabetes.
- Author
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Silander, Kaisa, Mohlke, Karen L., Scott, Laura J., Peck, Erin C., Hollstein, Pablo, Skol, Andrew D., Jackson, Anne U., Deloukas, Panagiotis, Hunt, Sarah, Stavrides, George, Chines, Peter S., Erdos, Michael R., Narisu, Narisu, Conneely, Karen N., Li, Chun, Fingerlin, Tasha E., Dhanjal, Sharanjeet K., Valle, Timo T., Bergman, Richard N., and Tuomilehto, Jaakko
- Subjects
TYPE 2 diabetes ,ENDOCRINE diseases ,DIABETES ,GENETICS ,LIVER cells - Abstract
The Finland-United States Investigation Of NIDDM Genetics (FUSION) study aims to identify genetic variants that predispose to type 2 diabetes by studying affected sibling pair families from Finland. Chromosome 20 showed our strongest initial evidence for linkage. It currently has a maximum logarithm of odds (LOD) score of 2.48 at 70 cM in a set of 495 families. In this study, we searched for diabetes susceptibility variant(s) at 20q13 by genotyping single nucleotide polymorphism (SNP) markers in case and control DNA pools. Of 291 SNPs successfully typed in a 7.5-Mb interval, the strongest association confirmed by individual genotyping was with SNP rs2144908, located 1.3 kb downstream of the primary β-cell promoter P2 of hepatocyte nuclear factor-4α (HNF4A). This SNP showed association with diabetes disease status (odds ratio [OR] 1.33, 95% CI 1.06-1.65, P = 0.011) and with several diabetes-related traits. Most of the evidence for linkage at 20q13 could be attributed to the families carrying the risk allele. We subsequently found nine additional associated SNPs spanning a 64-kb region, including the P2 and P1 promoters and exons 1-3. Our results and the independent observation of association of SNPs near the P2 promoter with diabetes in a separate study population of Ashkenazi Jewish origin suggests that variant(s) located near or within HNF4A increases susceptibility to type 2 diabetes. [ABSTRACT FROM AUTHOR]
- Published
- 2004
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33. Primacy of hepatic insulin resistance in the development of the metabolic syndrome induced by an isocaloric moderate-fat diet in the dog.
- Author
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Kim, Stella P., Ellmerer, Martin, Van Citters, Gregg W., and Bergman, Richard N.
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OBESITY ,INSULIN resistance ,TYPE 2 diabetes ,DOGS - Abstract
Obesity is highly correlated with insulin resistance and the development of type 2 diabetes. Insulin resistance will result in a decrease in insulin's ability to stimulate glucose uptake into peripheral tissue and will suppress glucose production by the liver. However, the developmerit of peripheral and hepatic insulin resistance relative to one another in the context of obesity-associated insulin resistance is not well understood. To examine this phenomena, we used the moderate fat-fed dog model, which has been shown to develop both subcutaneous and visceral adiposity and severe insulin resistance. Six normal dogs were fed an isocaloric diet with a modest increase in fat content for 12 weeks, and they were assessed at weeks 0, 6, and 12 for changes in insulin sensitivity and glucose turnover. By week 12 of the diet, there was a more than twofold increase in trunk adiposity as assessed by magnetic resonance imaging because of an accumulation in both subcutaneous and visceral fat depots with very little change in body weight. Fasting plasma insulin had increased by week 6 (150% of week 0) and remained increased up to week 12 of the study (170% of week 0). Surprisingly, there appeared to be no change in the rates of insulin-stimulated glucose uptake as measured by euglycemic-hyperinsulinemic clamps throughout the course of fat feeding. However, there was an increase in steady-state plasma insulin levels at weeks 6 and 12, indicating a moderate degree of peripheral insulin resistance. In contrast to the moderate defect seen in the periphery, there was a marked impairment in insulin's ability to suppress endogenous glucose production during the clamp such that by week 12 of the study, there was a complete inability of insulin to suppress glucose production. Our results indicate that a diet enriched with a moderate amount of fat results in the development of both subcutaneous and visceral adiposity, hyperinsulinemia, and a modest degree of peripheral insulin resistance. However, there is a complete inability of insulin to suppress hepatic gincose production during the clamp, suggesting that insulin resistance of the liver may be the primary defect in the development of insulin resistance associated with obesity. [ABSTRACT FROM AUTHOR]
- Published
- 2003
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- View/download PDF
34. Minimal model-based insulin sensitivity has greater heritability and a different genetic basis than homeostasis model assessment or fasting insulin.
- Author
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Bergman, Richard N., Zaccaro, Daniel J., Watanabe, Richard M., Haffner, Steven M., Saad, Mohammed F., Norris, Jill M., Wagenknecht, Lynne E., Hokanson, James E., Rotter, Jerome I., and Rich, Steven S.
- Subjects
- *
INSULIN resistance , *TYPE 2 diabetes , *CHRONIC diseases , *HYPERTENSION , *CARDIOVASCULAR diseases , *ARTERIOSCLEROSIS , *BIOLOGICAL models , *COMPARATIVE studies , *DISEASE susceptibility , *FASTING , *GLUCOSE tolerance tests , *HOMEOSTASIS , *INSULIN , *RESEARCH methodology , *MEDICAL cooperation , *RESEARCH , *PHENOTYPES , *EVALUATION research , *GLUCOSE intolerance - Abstract
Insulin resistance is an important risk factor for development of type 2 diabetes as well as other chronic conditions, including hypertension, cardiovascular disease, and colon cancer. To find genes for insulin resistance it is necessary to assess insulin action in large populations. We have previously measured insulin action in a large cohort of subjects (Insulin Resistance and Atherosclerosis Study [IRAS] Family Study) using the minimal model approach. In this study, we compare sensitivity from the minimal model (insulin sensitivity index [S(I)]) with the measure of insulin resistance emanating from the homeostasis model assessment (HOMA) approach. The former measure emerges from the glycemic response to endogenous and exogenous insulin; the latter is based solely on fasting measures of glucose and insulin. A total of 112 pedigrees were represented, including 1,362 individuals with full phenotypic assessment. Heritability of S(I) was significantly greater than that for HOMA (0.310 vs. 0.163) and for fasting insulin (0.171), adjusted for age, sex, ethnicity, and BMI. In addition, correlation between S(I) and either HOMA or fasting insulin was only approximately 50% accounted for by genetic factors, with the remainder accounted for by environment. Thus S(I), a direct measure of insulin sensitivity, is determined more by genetic factors rather than measures such as HOMA, which reflect fasting insulin. [ABSTRACT FROM AUTHOR]
- Published
- 2003
- Full Text
- View/download PDF
35. Accurate Assessment of β-Cells Function.
- Author
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Bergman, Richard N., Ader, Marilyn, Huecking, Katrin, and Van Citters, Gregg
- Subjects
- *
INSULIN resistance , *TYPE 2 diabetes , *PANCREATIC beta cells - Abstract
Only in the last decade did modeling studies predict, and knockout experiments confirm, that type 2 diabetes is a “2-hit” disease in which insulin resistance is necessarily accompanied by β-cell defect(s) preventing the compensatory upregulation of insulin secretion. This long-delayed insight was associated with the development of a constant, the “disposition index,” describing the β-cell sensitivity-secretion relationship as a rectangular hyperbola. Shifts in insulin sensitivity are accompanied by compensatory alterations in β-cell sensitivity to glucose. Insulin-sensitive subjects do not require a massive insulin response to exogenous glucose to maintain a normal blood glucose. But if their insulin sensitivity decreases by 80%, as in late pregnancy, they need a fivefold greater insulin response to achieve an identical disposition index. Women with gestational diabetes have an insulin response similar to that of normal volunteers; at first glance, this suggests similar islet function, but the utility of the disposition index is to normalize this response to the amplitude of third trimester insulin resistance, revealing severe β-cell deficiency. The index is a quantitative, convenient, and accurate tool in analyzing epidemiologlc data and identifying incipient impaired glucose tolerance. Separate major issues remain, however: the causes of insulin resistance, the causes of the failure of adequate β-cell compensation in type 2 diabetes, and the nature of the signal(s) from insulin-resistant tissues that fail to elicit the appropriate β-cell increment in sensitivity to glucose and other stimuli. The disposition index is likely to remain the most accurate physiologic measure for testing hypotheses and solutions to these challenges in whole organisms. Diabetes 51 (Suppl. 1):S212–S220, 2002 [ABSTRACT FROM AUTHOR]
- Published
- 2002
- Full Text
- View/download PDF
36. The peroxisome proliferator-activated receptor-gamma2 Pro12A1a variant: association with type 2 diabetes and trait differences.
- Author
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Douglas, Julie A., Erdos, Michael R., Watanabe, Richard M., Braun, Andi, Johnston, Cristy L., Oeth, Paul, Mohlke, Karen L., Valle, Timo T., Ehnholm, Christian, Buchanan, Thomas A., Bergman, Richard N., Collins, Francis S., Boehnke, Michael, Douglas, J A, Erdos, M R, Watanabe, R M, Braun, A, Johnston, C L, Oeth, P, and Mohlke, K L
- Subjects
TYPE 2 diabetes ,NUCLEAR receptors (Biochemistry) ,INSULIN - Abstract
Recent studies have identified a common proline-to-alanine substitution (Pro12Ala) in the peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2), a nuclear receptor that regulates adipocyte differentiation and possibly insulin sensitivity. The Pro12Ala variant has been associated in some studies with diabetes-related traits and/or protection against type 2 diabetes. We examined this variant in 935 Finnish subjects, including 522 subjects with type 2 diabetes, 193 nondiabetic spouses, and 220 elderly nondiabetic control subjects. The frequency of the Pro12Ala variant was significantly lower in diabetic subjects than in nondiabetic subjects (0.15 vs. 0.21; P = 0.001). We also compared diabetes-related traits between subjects with and without the Pro12Ala variant within subgroups. Among diabetic subjects, the variant was associated with greater weight gain after age 20 years (P = 0.023) and lower triglyceride levels (P = 0.033). Diastolic blood pressure was higher in grossly obese (BMI >40 kg/m2) diabetic subjects with the variant. In nondiabetic spouses, the variant was associated with higher fasting insulin (P = 0.033), systolic blood pressure (P = 0.021), and diastolic blood pressure (P = 0.045). These findings support a role for the PPAR-gamma2 Pro12Ala variant in the etiology of type 2 diabetes and the insulin resistance syndrome. [ABSTRACT FROM AUTHOR]
- Published
- 2001
- Full Text
- View/download PDF
37. Validation of methods for measurement of insulin secretion in humans in vivo.
- Author
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Kjems, Lise L., Christiansen, Erik, Volund, Aage, Bergman, Richard N., Madsbad, Sten, Kjems, L L, Christiansen, E, Vølund, A, Bergman, R N, and Madsbad, S
- Subjects
INSULIN ,TYPE 2 diabetes ,PANCREATIC beta cells ,PATHOLOGY ,SECRETION - Abstract
To detect and understand the changes in beta-cell function in the pathogenesis of type 2 diabetes, an accurate and precise estimation of prehepatic insulin secretion rate (ISR) is essential. There are two common methods to assess ISR, the deconvolution method (by Eaton and Polonsky)-considered the "gold standard"-and the combined model (by Vølund et al.). The deconvolution method is a 2-day method, which generally requires separate assessment of C-peptide kinetics, whereas the combined model is a single-day method that uses insulin and C-peptide data from a single test of interest. The validity of these mathematical techniques for quantification of insulin secretion have been tested in dogs, but not in humans. In the present studies, we examined the validity of both methods to recover the known infusion rates of insulin and C-peptide mimicking ISR during an oral glucose tolerance test. ISR from both the combined model and the deconvolution method were accurate, i.e., recovery of true ISR was not significantly different from 100%. Furthermore, both maximal and total ISRs from the combined model were strongly correlated to those obtained by the deconvolution method (r = 0.89 and r = 0.82, respectively). These results indicate that both approaches provide accurate assessment of prehepatic ISRs in type 2 diabetic patients and control subjects. A simplified version of the deconvolution method based on standard kinetic parameters for C-peptide (Van Cauter et al.) was compared with the 2-day deconvolution method, and a close agreement was found for the results of an oral glucose tolerance test. We also studied whether C-peptide kinetics are influenced by somatostatin infusion. The decay curves after bolus injection of exogenous biosynthetic human C-peptide, the kinetic parameters, and the metabolic clearance rate were similar whether measured during constant peripheral somatostatin infusion or without somatostatin infusion. Assessment of C-peptide kinetics can be performed without infusion of somatostatin, because the endogenous insulin concentration remains constant. Assessment of C-peptide kinetics with and without infusion of somatostatin results in nearly identical secretion rates for insulin during an oral glucose tolerance test. [ABSTRACT FROM AUTHOR]
- Published
- 2000
- Full Text
- View/download PDF
38. Accurate measurement of endogenous insulin secretion does not require separate assessment of C-peptide kinetics.
- Author
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Watanabe, Richard M., Bergman, Richard N., Watanabe, R M, and Bergman, R N
- Subjects
- *
INSULIN , *ISLANDS of Langerhans , *TYPE 2 diabetes , *SECRETION - Abstract
The implication of beta-cell failure as an early defect in type 2 diabetes exacerbates the need for accurate but facile assessment of islet cell secretory rate, particularly in large group studies in which individual assessment of C-peptide kinetics is impractical. This study was designed to examine whether it is possible to obtain accurate secretory rates from the extended combined model, which provides insulin and C-peptide kinetics from plasma measurements of the two peptides. Equimolar intraportal infusions of insulin and C-peptide that are designed to simulate insulin secretion rates during both oral and intravenous glucose tolerance tests were used to generate plasma insulin and C-peptide data in conscious dogs that were examined under clamped glucose conditions. The plasma peptide kinetics were analyzed using the extended combined model to generate estimates of prehepatic insulin secretion that were then compared with the known intraportal infusion rates. The extended combined model was able to reproduce the known intraportal infusion profiles. The model-predicted rates were similar to those calculated with methods that require separate assessment of C-peptide kinetics. Simulation results supported lesser clearance of insulin during rapid changes of portal insulin (as measured by an intravenous glucose tolerance test) versus slow changes in portal insulin (as measured by an oral glucose tolerance test). The extended combined model accurately calculates prehepatic insulin appearance. It may be possible to apply this approach to large studies of beta-cell function designed to identify changes in islet function in subjects at risk for diabetes. Such an approach could strengthen epidemiological and genetic studies of the pathogenesis of diabetes. [ABSTRACT FROM AUTHOR]
- Published
- 2000
- Full Text
- View/download PDF
39. Prolonged elevation of plasma free fatty acids impairs pancreatic beta-cell function in obese nondiabetic humans but not in individuals with type 2 diabetes.
- Author
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Carpentier, Andre, Mittelman, Steven D., Bergman, Richard N., Giacca, Adria, Lewis, Gary F., Carpentier, A, Mittelman, S D, Bergman, R N, Giacca, A, and Lewis, G F
- Subjects
BLOOD lipids ,PANCREATIC beta cells ,TYPE 2 diabetes - Abstract
Our recent in vivo observations in healthy nonobese humans have demonstrated that prolonged elevation of plasma free fatty acids (FFAs) results in diminished glucose-stimulated insulin secretion (GSIS) when the FFA-mediated decrease in insulin sensitivity is taken into account. In the present study, we investigated whether obese individuals and patients with type 2 diabetes are more sensitive than healthy control subjects to the inhibitory effect of prolonged elevation of plasma FFAs on GSIS. In seven patients with type 2 diabetes and seven healthy nondiabetic obese individuals, we assessed GSIS with a programmed graded intravenous glucose infusion on two occasions, 6-8 weeks apart, with and without a prior 48-h infusion of heparin and Intralipid, which was designed to raise plasma FFA concentration approximately twofold over basal. The nondiabetic obese subjects had a significant 21% decrease in GSIS (P = 0.0008) with the heparin and Intralipid infusion, associated with a decrease in whole body insulin clearance. The impairment in GSIS was evident at low (<11 mmol/l) but not at higher plasma glucose concentrations. In contrast, the patients with type 2 diabetes had a slight increase in GSIS (P = 0.027) and no change in insulin clearance, although there was marked interindividual variability in response. Plasma proinsulin concentrations measured in a subset of subjects were not altered in either group by the infusion of heparin and Intralipid. In summary, 1) obese nondiabetic individuals are susceptible to a desensitization of GSIS with heparin and Intralipid infusion, and 2) patients with type 2 diabetes do not demonstrate such susceptibility when FFAs are elevated approximately twofold above basal with heparin and Intralipid. Our results suggest that FFAs could play an important role in the development of beta-cell failure in obese individuals who are at risk for developing type 2 diabetes. They do not, however, seem to further deteriorate the beta-cell function of patients who already have established type 2 diabetes and may even result in a slight increase in GSIS in this latter group. [ABSTRACT FROM AUTHOR]
- Published
- 2000
- Full Text
- View/download PDF
40. A Peripheral CB1R Antagonist Increases Lipolysis, Oxygen Consumption Rate, and Markers of Beiging in 3T3-L1 Adipocytes Similar to RIM, Suggesting that Central Effects Can Be Avoided.
- Author
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Paszkiewicz, Rebecca L., Bergman, Richard N., Santos, Roberta S., Frank, Aaron P., Woolcott, Orison O., Iyer, Malini S., Stefanovski, Darko, Clegg, Deborah J., and Kabir, Morvarid
- Subjects
- *
LIPOLYSIS , *OXYGEN consumption , *FAT cells , *ADENOSINE triphosphatase , *ADIPOSE tissues , *CELL size , *TYPE 2 diabetes - Abstract
With the increased prevalence of obesity and related co-morbidities, such as type 2 diabetes (T2D), worldwide, improvements in pharmacological treatments are necessary. The brain- and peripheral-cannabinoid receptor 1 (CB1R) antagonist rimonabant (RIM) has been shown to induce weight loss and improve glucose homeostasis. We have previously demonstrated that RIM promotes adipose tissue beiging and decreased adipocyte cell size, even during maintenance on a high-fat diet. Given the adverse side-effects of brain-penetrance with RIM, in this study we aimed to determine the site of action for a non-brain-penetrating CB1R antagonist AM6545. By using in vitro assays, we demonstrated the direct effects of this non-brain-penetrating CB1R antagonist on cultured adipocytes. Specifically, we showed, for the first time, that AM6545 significantly increases markers of adipose tissue beiging, mitochondrial biogenesis, and lipolysis in 3T3-L1 adipocytes. In addition, the oxygen consumption rate (OCR), consisting of baseline respiratory rate, proton leak, maximal respiratory capacity, and ATP synthase activity, was greater for cells exposed to AM6545, demonstrating greater mitochondrial uncoupling. Using a lipolysis inhibitor during real-time OCR measurements, we determined that the impact of CB1R antagonism on adipocytes is driven by increased lipolysis. Thus, our data suggest the direct role of CB1R antagonism on adipocytes does not require brain penetrance, supporting the importance of focus on peripheral CB1R antagonism pharmacology for reducing the incidence of obesity and T2D. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
41. Genome-Wide Association Scan Meta-Analysis Identifies Three Loci Influencing Adiposity and Fat Distribution
- Author
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Lindgren, Cecilia M., Heid, Iris M., Randall, Joshua C., Lamina, Claudia, Steinthorsdottir, Valgerdur, Speliotes, Elizabeth K., Thorleifsson, Gudmar, Willer, Cristen J., Herrera, Blanca M., Jackson, Anne U., Lim, Noha, Scheet, Paul, Soranzo, Nicole, Amin, Najaf, Aulchenko, Yurii S., Chambers, John C., Drong, Alexander, Luan, Jian'an, Rivadeneira, Fernando, Sanna, Serena, Timpson, Nicholas J., Zillikens, M. Carola, Almgren, Peter, Bandinelli, Stefania, Bennett, Amanda J., Bergman, Richard N., Bonnycastle, Lori L., Bumpstead, Suzannah J., Chanock, Stephen J., Cherkas, Lynn, Chines, Peter, Coin, Lachlan, Cooper, Cyrus, Crawford, Gabriel, Doering, Angela, Dominiczak, Anna, Doney, Alex S. F., Ebrahim, Shah, Elliott, Paul, Erdos, Michael R., Estrada, Karol, Ferrucci, Luigi, Fischer, Guido, Forouhi, Nita G., Gieger, Christian, Grallert, Harald, Groves, Christopher J., Grundy, Scott, Guiducci, Candace, Hadley, David, Hamsten, Anders, Havulinna, Aki S., Holle, Rolf, Holloway, John W., Illig, Thomas, Isomaa, Bo, Jacobs, Leonie C., Jameson, Karen, Jousilahti, Pekka, Karpe, Fredrik, Kuusisto, Johanna, Laitinen, Jaana, Lathrop, G. Mark, Lawlor, Debbie A., Mangino, Massimo, McArdle, Wendy L., Meitinger, Thomas, Morken, Mario A., Morris, Andrew P., Munroe, Patricia, Narisu, Narisu, Nordström, Anna, Nordström, Peter, Oostra, Ben A., Palmer, Colin N. A., Payne, Felicity, Peden, John F., Prokopenko, Inga, Renström, Frida, Ruokonen, Aimo, Salomaa, Veikko, Sandhu, Manjinder S., Scuteri, Angelo, Silander, Kaisa, Song, Kijoung, Stringham, Heather M., Swift, Amy J., Tuomi, Tiinamaija, Uda, Manuela, Vollenweider, Peter, Waeber, Gerard, Wallace, Chris, Walters, G. Bragi, Weedon, Michael N., Witteman, Jacqueline C. M., Zhang, Cuilin, Zhang, Weihua, Caulfield, Mark J., Collins, Francis S., Davey Smith, George, Day, Ian N. M., Franks, Paul W., Hattersley, Andrew T., Jarvelin, Marjo-Riitta, Kong, Augustine, Kooner, Jaspal S., Laakso, Markku, Lakatta, Edward, Mooser, Vincent, Morris, Andrew D., Peltonen, Leena, Samani, Nilesh J., Spector, Timothy D., Strachan, David P., Tanaka, Toshiko, Tuomilehto, Jaakko, Uitterlinden, André G., van Duijn, Cornelia M., Wareham, Nicholas J., Waterworth, Dawn M., Boehnke, Michael, Deloukas, Panos, Groop, Leif, Thorsteinsdottir, Unnur, Schlessinger, David, Wichmann, H.-Erich, Frayling, Timothy M., Abecasis, Gonçalo R., Loos, Ruth J. F., Stefansson, Kari, Mohlke, Karen L., Barroso, Inês, Hirschhorn, Joel Naom, McCarthy, Mark I., Watkins, Hugh, The Wellcome Trust Case Control Consortium, Hunter, David J., Hu, Frank B., Yuan, Xin, Scott, Laura J., Hofman, Albert, Zhao, Jing Hua, Lyon, Helen N, and Qi, Lu
- Subjects
diabetes and endocrinology ,obesity ,type 2 diabetes ,complex traits ,genetics and genomics - Abstract
To identify genetic loci influencing central obesity and fat distribution, we performed a meta-analysis of 16 genome-wide association studies (GWAS, N = 38,580) informative for adult waist circumference (WC) and waist–hip ratio (WHR). We selected 26 SNPs for follow-up, for which the evidence of association with measures of central adiposity (WC and/or WHR) was strong and disproportionate to that for overall adiposity or height. Follow-up studies in a maximum of 70,689 individuals identified two loci strongly associated with measures of central adiposity; these map near TFAP2B (WC, P = 1.9×\(10^{-11}\)) and MSRA (WC, P = 8.9×\(10^{-9}\)). A third locus, near LYPLAL1, was associated with WHR in women only (P = 2.6×\(10^{-8}\)). The variants near TFAP2B appear to influence central adiposity through an effect on overall obesity/fat-mass, whereas LYPLAL1 displays a strong female-only association with fat distribution. By focusing on anthropometric measures of central obesity and fat distribution, we have identified three loci implicated in the regulation of human adiposity.
- Published
- 2009
- Full Text
- View/download PDF
42. Erratum. Hypothesis: Role of Reduced Hepatic Insulin Clearance in the Pathogenesis of Type 2 Diabetes. Diabetes 2019;68:1709-1716.
- Author
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Bergman, Richard N, Piccinini, Francesca, Kabir, Morvarid, Kolka, Cathryn M, and Ader, Marilyn
- Subjects
- *
TYPE 2 diabetes , *PATHOLOGY , *INSULIN , *DIABETES - Abstract
A correction is presented to the article related to role of Reduced Hepatic Insulin Clearance in the Pathogenesis of Type 2 Diabetes that published in 2019 issue of the periodical.
- Published
- 2019
- Full Text
- View/download PDF
43. Obesity, insulin resistance, and the pathway to type 2 diabetes.
- Author
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Bergman, Richard N.
- Subjects
- *
OBESITY , *TYPE 2 diabetes - Abstract
An abstract of the article "Obesity, insulin resistance, and the pathway to type 2 diabetes," by Richard N. Bergman is presented.
- Published
- 2012
- Full Text
- View/download PDF
44. FGF19 action in the brain induces insulin-independent glucose lowering.
- Author
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Morton, Gregory J., Matsen, Miles E., Bracy, Deanna P., Meek, Thomas H., Nguyen, Hong T., Stefanovski, Darko, Bergman, Richard N., Wasserman, David H., and Schwartz, Michael W.
- Subjects
- *
TYPE 2 diabetes , *GLUCOSE tolerance tests , *HYPOGLYCEMIC agents , *INSULIN resistance , *LEPTIN , *BRAIN chemistry - Abstract
Insulin-independent glucose disposal (referred to as glucose effectiveness [GE]) is crucial for glucose homeostasis and, until recently, was thought to be invariable. However, GE is reduced in type 2 diabetes and markedly decreased in leptin-deficient ob/ob mice. Strategies aimed at increasing GE should therefore be capable of improving glucose tolerance in these animals. The gut-derived hormone FGF19 has previously been shown to exert potent antidiabetic effects in ob/ob mice. In ob/ob mice, we found that systemic FGF19 administration improved glucose tolerance through its action in the brain and that a single, low-dose i.c.v. injection of FGF19 dramatically improved glucose intolerance within 2 hours. Minimal model analysis of glucose and insulin data obtained during a frequently sampled i.v. glucose tolerance test showed that the antidiabetic effect of i.c.v. FGF19 was solely due to increased GE and not to changes of either insulin secretion or insulin sensitivity. The mechanism underlying this effect appears to involve increased metabolism of glucose to lactate. Together, these findings implicate the brain in the antidiabetic action of systemic FGF19 and establish the brain's capacity to rapidly, potently, and selectively increase insulin-independent glucose disposal. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
45. Evaluation of SLC2A10 (GLUT10) as a candidate gene for type 2 diabetes and related traits in Finns
- Author
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Mohlke, Karen L., Skol, Andrew D., Scott, Laura J., Valle, Timo T., Bergman, Richard N., Tuomilehto, Jaakko, Boehnke, Michael, and Collins, Francis S.
- Subjects
- *
TYPE 2 diabetes , *ENDOCRINE diseases , *CARBOHYDRATE intolerance , *HYPOGLYCEMIC agents - Abstract
Abstract: The SLC2A10 gene encodes a glucose transporter and is located on chromosome 20q13, where evidence has been found for linkage to type 2 diabetes (T2D) in multiple studies. We investigated SLC2A10 as a T2D candidate gene in Finns. We did not confirm the previously reported association between Ala206Thr and fasting insulin and we observed no statistically significant evidence for T2D association with any single marker. We tested haplotypes for association with diabetes-related traits and observed no excess of significant results. [Copyright &y& Elsevier]
- Published
- 2005
- Full Text
- View/download PDF
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