Graeme I Bell

Publications of Graeme I Bell

• Three Strikes and You're Cured.

  Authors: Anita S Chong, Graeme I Bell

  Science translational medicine. 05/2012; 4(133):133fs12.

  New research shows that in a mouse model of type 1 diabetes, it may be possible to abrogate autoimmunity and then exploit the ability of pancreatic β cells to regenerate, thereby restoring bloodNew research shows that in a mouse model of type 1 diabetes, it may be possible to abrogate autoimmunity and then exploit the ability of pancreatic β cells to regenerate, thereby restoring blood glucose regulation.

• An in vivo cis-Regulatory Screen at the Type 2 Diabetes Associated TCF7L2 Locus Identifies Multiple Tissue-Specific Enhancers.

  Authors: Daniel Savic, Graeme I Bell, Marcelo A Nobrega

  PloS one. 01/2012; 7(5):e36501.

  Genome-wide association studies (GWAS) have repeatedly shown an association between non-coding variants in the TCF7L2 locus and risk for type 2 diabetes (T2D), implicating a role for cis-regulatoryGenome-wide association studies (GWAS) have repeatedly shown an association between non-coding variants in the TCF7L2 locus and risk for type 2 diabetes (T2D), implicating a role for cis-regulatory variation within this locus in disease etiology. Supporting this hypothesis, we previously localized complex regulatory activity to the TCF7L2 T2D-associated interval using an in vivo bacterial artificial chromosome (BAC) enhancer-trapping reporter strategy. To follow-up on this broad initial survey of the TCF7L2 regulatory landscape, we performed a fine-mapping enhancer scan using in vivo mouse transgenic reporter assays. We functionally interrogated approximately 50% of the sequences within the T2D-associated interval, utilizing sequence conservation within this 92-kb interval to determine the regulatory potential of all evolutionary conserved sequences that exhibited conservation to the non-eutherian mammal opossum. Included in this study was a detailed functional interrogation of sequences spanning both protective and risk alleles of single nucleotide polymorphism (SNP) rs7903146, which has exhibited allele-specific enhancer function in pancreatic beta cells. Using these assays, we identified nine segments regulating various aspects of the TCF7L2 expression profile and that constitute nearly 70% of the sequences tested. These results highlight the regulatory complexity of this interval and support the notion that a TCF7L2 cis-regulatory disruption leads to T2D predisposition.

• Neonatal diabetes: an expanding list of genes allows for improved diagnosis and treatment.

  Authors: Siri Atma W Greeley, Rochelle N Naylor, Louis H Philipson, Graeme I Bell

  Current diabetes reports. 12/2011; 11(6):519-32.

  There has been major progress in recent years uncovering the genetic causes of diabetes presenting in the first year of life. Twenty genes have been identified to date. The most common causesThere has been major progress in recent years uncovering the genetic causes of diabetes presenting in the first year of life. Twenty genes have been identified to date. The most common causes accounting for the majority of cases are mutations in the genes encoding the two subunits of the ATP-sensitive potassium channel (K(ATP)), KCNJ11 and ABCC8, and the insulin gene (INS), as well as abnormalities in chromosome 6q24. Patients with activating mutations in KCNJ11 and ABCC8 can be treated with oral sulfonylureas in lieu of insulin injections. This compelling example of personalized genetic medicine leading to improved glucose regulation and quality of life may-with continued research-be repeated for other forms of neonatal diabetes in the future.

• MODY: history, genetics, pathophysiology, and clinical decision making.

  Authors: Stefan S Fajans, Graeme I Bell

  Diabetes care. 08/2011; 34(8):1878-84.

• Alterations in TCF7L2 expression define its role as a key regulator of glucose metabolism.

  Authors: Daniel Savic, Honggang Ye, Ivy Aneas, Soo-Young Park, Graeme I Bell, Marcelo A Nobrega

  Genome research. 06/2011; 21(9):1417-25.

  Genome-wide association studies (GWAS) have consistently implicated noncoding variation within the TCF7L2 locus with type 2 diabetes (T2D) risk. While this locus represents the strongest geneticGenome-wide association studies (GWAS) have consistently implicated noncoding variation within the TCF7L2 locus with type 2 diabetes (T2D) risk. While this locus represents the strongest genetic determinant for T2D risk in humans, it remains unclear how these noncoding variants affect disease etiology. To test the hypothesis that the T2D-associated interval harbors cis-regulatory elements controlling TCF7L2 expression, we conducted in vivo transgenic reporter assays to characterize the TCF7L2 regulatory landscape. We found that the 92-kb genomic interval associated with T2D harbors long-range enhancers regulating various aspects of the spatial-temporal expression patterns of TCF7L2, including expression in tissues involved in the control of glucose homeostasis. By selectively deleting this interval, we establish a critical role for these enhancers in robust TCF7L2 expression. To further determine whether variation in Tcf7l2 expression may lead to diabetes, we developed a Tcf7l2 copy-number allelic series in mice. We show that a null Tcf7l2 allele leads, in a dose-dependent manner, to lower glycemic profiles. Tcf7l2 null mice also display enhanced glucose tolerance coupled to significantly lowered insulin levels, suggesting that these mice are protected against T2D. Confirming these observations, transgenic mice harboring multiple Tcf7l2 copies and overexpressing this gene display reciprocal phenotypes, including glucose intolerance. These results directly demonstrate that Tcf7l2 plays a role in regulating glucose tolerance, suggesting that overexpression of this gene is associated with increased risk of T2D. These data highlight the role of enhancer elements as mediators of T2D risk in humans, strengthening the evidence that variation in cis-regulatory elements may be a paradigm for genetic predispositions to common disease.

• HLA-DQ haplotypes differ by ethnicity in patients with childhood-onset diabetes.

  Authors: Rebecca B Lipton, Melinda Drum, Siri Atma W Greeley, Kirstie K Danielson, Graeme I Bell, William A Hagopian

  Pediatric diabetes. 03/2011; 12(4 Pt 2):388-95.

  To understand the etiology of childhood-onset diabetes, we examined genetic risk markers, autoantibodies, and β-cell function in a mixed race group of young patients. One hundred and forty-fiveTo understand the etiology of childhood-onset diabetes, we examined genetic risk markers, autoantibodies, and β-cell function in a mixed race group of young patients. One hundred and forty-five patients aged 0-17 at diagnosis (54% African American, 22% Caucasian, 16% Latino, 8% mixed-other) were studied at mean duration 6.9 ± 5.7 (range 0.1-28.5) yr, including human leukocyte antigen (HLA)-DQA1-DQB1 genotyping, stimulated C peptide (CP), glutamic acid decarboxylase, and insulinoma-associated antigen 2 antibodies (ABs). Based on no residual β-cell function (CP-) and islet autoantibodies (AB+), 111 patients were classified with type 1 diabetes mellitus (T1DM), 22 were CP+ and AB- and thus considered to have type 2 diabetes mellitus (T2DM), and 12 patients had features of both T1DM and T2DM or mixed phenotype. Based on the presence of two high-risk HLA-DQA1/B1 haplotypes, 39% of African Americans, 81% of Caucasians, 70% of Latinos, and 67% of mixed-others were at high genetic risk. In patients with T1DM, 41% of African Americans, 80% of Caucasians, 73% of Latinos, and 63% of mixed-others were genetically susceptible. Thirty-one percent of African Americans, including 29% of those with T1DM, could not be characterized because their haplotypes had unknown T1DM associations. These unusual haplotypes comprised 11% in T1DM, 14% in T2DM, and 8% in patients with mixed phenotype. Fifty-nine percent of childhood-onset patients with T1DM were identified with high genetic risk based on known HLA-DQA1/B1 associations. Many non-Caucasian patients carry HLA-DQ alleles whose association with T1DM is undetermined. Genetic approaches can provide insights into the etiology and appropriate treatment of childhood-onset diabetes but only if sufficient data are available in diverse ethnic groups.

• Onset features and subsequent clinical evolution of childhood diabetes over several years.

  Authors: Rebecca B Lipton, Melinda L Drum, Kirstie K Danielson, Siri Aw Greeley, Graeme I Bell, William A Hagopian

  Pediatric diabetes. 03/2011; 12(4 Pt 1):326-34.

  To explore whether it is possible to predict a child's eventual diabetes phenotype using characteristics at initial presentation, we reassessed 111 young patients on average 7.8 ± 4.2 (2.2-19.7)To explore whether it is possible to predict a child's eventual diabetes phenotype using characteristics at initial presentation, we reassessed 111 young patients on average 7.8 ± 4.2 (2.2-19.7) [mean ± SD (range)] years after diagnosis. Medical records at diagnosis for 111 patients, aged 0-17, were compared with their follow-up characteristics including stimulated C-peptide (CP) and islet autoantibodies (AB). Initially, 18 patients were obese; 9 displayed other type 2 diabetes (T2DM) features (polycystic ovary syndrome, acanthosis, diagnosed T2DM); the remaining 84 had a classic type 1 diabetes (T1DM) presentation. At follow-up, 83 patients (75%) with no measured CP were classified as T1DM; 17 (15%) were CP+ and AB- and thus considered T2DM. Eleven patients with both T1DM and T2DM features were classified as having mixed diabetes phenotype (MDM). One-fifth (22 subjects) changed presumed phenotype at follow-up. In multivariable models, T1DM patients were younger at diagnosis, had higher initial glucose values, were more likely to have experienced ketoacidosis, and less likely to be obese or of African American ethnicity. Ten percent of subjects had MDM and 15% had T2DM at ∼8 years' duration. Although no onset feature was completely reliable, ketoacidosis and hyperglycemia were more likely to predict T1DM; obesity and African American ethnicity made T2DM more likely. At diagnosis, features of T2DM in addition to obesity were strongly predictive of eventual T2DM phenotype. Given the significant percentage who changed or had mixed phenotype, careful tracking of all young people with diabetes is essential to correctly determine eventual disease type.

• Erratum to: Clinical and molecular genetics of neonatal diabetes due to mutations in the insulin gene.

  Authors: Julie Støy, Donald F Steiner, Soo-Young Park, Honggang Ye, Louis H Philipson, Graeme I Bell

  Reviews in endocrine & metabolic disorders. 02/2011; 13(1):79-81.

• The cost-effectiveness of personalized genetic medicine: the case of genetic testing in neonatal diabetes.

  Authors: Siri Atma W Greeley, Priya M John, Aaron N Winn, Joseph Ornelas, Rebecca B Lipton, Louis H Philipson, Graeme I Bell, Elbert S Huang

  Diabetes care. 01/2011; 34(3):622-7.

  Neonatal diabetes mellitus is a rare form of diabetes diagnosed in infancy. Nearly half of patients with permanent neonatal diabetes have mutations in the genes for the ATP-sensitive potassiumNeonatal diabetes mellitus is a rare form of diabetes diagnosed in infancy. Nearly half of patients with permanent neonatal diabetes have mutations in the genes for the ATP-sensitive potassium channel (KCNJ11 and ABCC8) that allow switching from insulin to sulfonylurea therapy. Although treatment conversion has dramatic benefits, the cost-effectiveness of routine genetic testing is unknown. We conducted a societal cost-utility analysis comparing a policy of routine genetic testing to no testing among children with permanent neonatal diabetes. We used a simulation model of type 1 diabetic complications, with the outcome of interest being the incremental cost-effectiveness ratio (ICER, $/quality-adjusted life-year [QALY] gained) over 30 years of follow-up. In the base case, the testing policy dominated the no-testing policy. The testing policy was projected to bring about quality-of-life benefits that enlarged over time (0.32 QALYs at 10 years, 0.70 at 30 years) and produced savings in total costs that were present as early as 10 years ($12,528 at 10 years, $30,437 at 30 years). Sensitivity analyses indicated that the testing policy would remain cost-saving as long as the prevalence of the genetic defects remained >3% and would retain an ICER <$200,000/QALY at prevalences between 0.7 and 3%. Genetic testing in neonatal diabetes improves quality of life and lowers costs. This paradigmatic case study highlights the potential economic impact of applying the concepts of personalized genetic medicine to other disorders in the future.

• Clinical and molecular genetics of neonatal diabetes due to mutations in the insulin gene.

  Authors: Julie Støy, Donald F Steiner, Soo-Young Park, Honggang Ye, Louis H Philipson, Graeme I Bell

  Reviews in endocrine & metabolic disorders. 10/2010; 11(3):205-15.

  Over the last decade our insight into the causes of neonatal diabetes has greatly expanded. Neonatal diabetes was once considered a variant of type 1 diabetes that presented early in life. RecentOver the last decade our insight into the causes of neonatal diabetes has greatly expanded. Neonatal diabetes was once considered a variant of type 1 diabetes that presented early in life. Recent advances in our understanding of this disorder have established that neonatal diabetes is not an autoimmune disease, but rather is a monogenic form of diabetes resulting from mutations in a number of different genes encoding proteins that play a key role in the normal function of the pancreatic beta-cell. Moreover, a correct genetic diagnosis can affect treatment and clinical outcome. This is especially true for patients with mutations in the genes KCNJ11 or ABCC8 that encode the two protein subunits (Kir6.2 and SUR1, respectively) of the ATP-sensitive potassium channel. These patients can be treated with oral sulfonylurea drugs with better glycemic control and quality of life. Recently, mutations in the insulin gene (INS) itself have been identified as another cause of neonatal diabetes. In this article, we review the role of INS mutations in the pathophysiology of neonatal diabetes.

• Obesity and hyperinsulinemia in a family with pancreatic agenesis and MODY caused by the IPF1 mutation Pro63fsX60.

  Authors: Stefan S Fajans, Graeme I Bell, Veronica P Paz, Jennifer E Below, Nancy J Cox, Catherine Martin, Inas H Thomas, Ming Chen

  Translational research : the journal of laboratory and clinical medicine. 07/2010; 156(1):7-14.

  We studied the genetic and clinical features of diabetic subjects in a 5-generation Michigan-Kentucky pedigree ascertained through a proband with pancreatic agenesis and homozygous for the IPF1We studied the genetic and clinical features of diabetic subjects in a 5-generation Michigan-Kentucky pedigree ascertained through a proband with pancreatic agenesis and homozygous for the IPF1 mutation Pro63fsx60. Diabetic and nondiabetic family members were genotyped and phenotyped. We also carried out genetic studies to determine the history of the IPF1 mutation in the Michigan-Kentucky family and a Virginia family with the same mutation. We identified 110 individuals; 34 are currently being treated for diabetes and 10 of these are Pro63fsX60 carriers (ie, MODY4). Subjects with MODY as well as those with type 2 diabetes are characterized by obesity and hyperinsulinemia. Genetic studies suggest that the IPF1 mutation was inherited from an ancestor common to both the Michigan-Kentucky and Virginia families. MODY4 and type 2 diabetes in the Michigan-Kentucky pedigree are associated with obesity and hyperinsulinemia. Obesity and hyperinsulinemia have been observed occasionally in other subtypes of MODY, which suggests that hyperinsulinemia may be a general phenomenon when obesity occurs in MODY subjects. Hypoinsulinemia in nonobese MODY subjects seems to be caused by a functional defect in the beta cell. Genetic testing should be considered in multigenerational obese diabetic subjects, particularly when such families contain young diabetic members.

• Calpain-10 is a component of the obesity-related quantitative trait locus Adip1.

  Authors: James M Cheverud, Gloria L Fawcett, Joseph P Jarvis, Elizabeth A Norgard, Mihaela Pavlicev, L Susan Pletscher, Kenneth S Polonsky, Honggang Ye, Graeme I Bell, Clay F Semenkovich

  Journal of lipid research. 05/2010; 51(5):907-13.

  We previously mapped Adip1, an obesity quantitative trait locus (QTL), to the central portion of murine chromosome 1 containing the calpain-10 (Capn10) gene. Human studies have associated calpain-10We previously mapped Adip1, an obesity quantitative trait locus (QTL), to the central portion of murine chromosome 1 containing the calpain-10 (Capn10) gene. Human studies have associated calpain-10 (CAPN10) variants with type 2 diabetes and various metabolic traits. We performed a quantitative hybrid complementation test (QHCT) to determine whether differences attributed to Adip1 are the result of variant Capn10 alleles in LG/J and SM/J mice. We crossed LG/J and SM/J to wild-type (C57BL/6J) and Capn10 knockout (Capn10(-/-)) mice to form four F(1) hybrid groups: LG/J by wild-type, LG/J by Capn10(-/-), SM/J by wild-type, and SM/J by Capn10(-/-). We performed a two-way ANOVA with the experimental strain, tester strain, and their interaction as the factors. Significant interaction indicates a quantitative failure to complement. We found failure to complement for fat, organ, and body weights, and leptin, female free fatty acid, and triglyceride levels. Capn10(-/-) resulted in heavier weights and higher serum levels in LG/J crosses but not in SM/J crosses. For glucose tolerance and insulin response tests, the Capn10(-/-) allele resulted in lower glucose levels in crosses with SM/J but had no effect in the LG/J crosses. Differences between the LG/J and SM/J Capn10 alleles are the likely source of some of the QTL effects mapped to Adip1 in the LG/J-by-SM/J cross. Capn10 plays an important role in regulating obesity and diabetes in mice.

• Neonatal diabetes mellitus: a model for personalized medicine.

  Authors: Siri Atma W Greeley, Susan E Tucker, Rochelle N Naylor, Graeme I Bell, Louis H Philipson

  Trends in endocrinology and metabolism: TEM. 04/2010; 21(8):464-72.

  Neonatal diabetes mellitus occurs in approximately 1 out of every 100,000 live births. It can be either permanent or transient, and recent studies indicate that is likely to have an underlyingNeonatal diabetes mellitus occurs in approximately 1 out of every 100,000 live births. It can be either permanent or transient, and recent studies indicate that is likely to have an underlying genetic cause, particularly when diagnosed before 6 months of age. Permanent neonatal diabetes is most commonly due to activating mutations in either of the genes encoding the two subunits of the ATP-sensitive potassium channel. In most of these patients, switching from insulin to oral sulfonylurea therapy leads to improved metabolic control, as well as possible amelioration of occasional associated neurodevelopmental disabilities. It remains to be determined what is the most appropriate treatment of other causes. The diagnosis and treatment of neonatal diabetes, therefore, represents a model for personalized medicine.

• Mutant proinsulin proteins associated with neonatal diabetes are retained in the endoplasmic reticulum and not efficiently secreted.

  Authors: Soo-Young Park, Honggang Ye, Donald F Steiner, Graeme I Bell

  Biochemical and biophysical research communications. 01/2010; 391(3):1449-54.

  Mutations in the preproinsulin protein that affect processing of preproinsulin to proinsulin or lead to misfolding of proinsulin are associated with diabetes. We examined the subcellular localizationMutations in the preproinsulin protein that affect processing of preproinsulin to proinsulin or lead to misfolding of proinsulin are associated with diabetes. We examined the subcellular localization and secretion of 13 neonatal diabetes-associated human proinsulin proteins (A24D, G32R, G32S, L35P, C43G, G47V, F48C, G84R, R89C, G90C, C96Y, S101C and Y108C) in rat INS-1 insulinoma cells. These mutant proinsulin proteins accumulate in the endoplasmic reticulum (ER) and are poorly secreted except for G84R and in contrast to wild-type and hyperproinsulinemia-associated mutant proteins (H34D and R89H) which were sorted to secretory granules and efficiently secreted. We also examined the effect of C96Y mutant proinsulin on the synthesis and secretion of wild-type insulin and observed a dominant-negative effect of the mutant proinsulin on the synthesis and secretion of wild-type insulin due to induction of the unfolded protein response and resulting attenuation of overall translation.

• Identification of Diabetic Retinopathy Genes through a Genome-Wide Association Study among Mexican-Americans from Starr County, Texas.

  Authors: Yi-Ping Fu, D Michael Hallman, Victor H Gonzalez, Barbara E K Klein, Ronald Klein, M Geoffrey Hayes, Nancy J Cox, Graeme I Bell, Craig L Hanis

  Journal of ophthalmology. 01/2010; 2010.

  To identify genetic loci for severe diabetic retinopathy, 286 Mexican-Americans with type 2 diabetes from Starr County, Texas, completed physical examinations including fundus photography forTo identify genetic loci for severe diabetic retinopathy, 286 Mexican-Americans with type 2 diabetes from Starr County, Texas, completed physical examinations including fundus photography for diabetic retinopathy grading. Individuals with moderate-to-severe non-proliferative and proliferative diabetic retinopathy were defined as cases. Direct genotyping was performed using the Affymetrix GeneChip Human Mapping 100 K Set, and SNPs passing quality control criteria were used to impute markers available in HapMap Phase III Mexican population (MXL) in Los Angeles, California. Two directly genotyped markers were associated with severe diabetic retinopathy at a P-value less than .0001: SNP rs2300782 (P = 6.04 × 10(-5)) mapped to an intron region of CAMK4 (calcium/calmodulin-dependent protein kinase IV) on chromosome 5, and SNP rs10519765 (P = 6.21 × 10(-5)) on chromosomal 15q13 in the FMN1 (formin 1) gene. Using well-imputed markers based on the HapMap III Mexican population, we identified an additional 32 SNPs located in 11 chromosomal regions with nominal association with severe diabetic retinopathy at P-value less than .0001. None of these markers were located in traditional candidate genes for diabetic retinopathy or diabetes itself. However, these signals implicate genes involved in inflammation, oxidative stress and cell adhesion for the development and progression of diabetic retinopathy.

• Glycemic control promotes pancreatic beta-cell regeneration in streptozotocin-induced diabetic mice.

  Authors: Eric J Grossman, David D Lee, Jing Tao, Raphael A Wilson, Soo-Young Park, Graeme I Bell, Anita S Chong

  PloS one. 01/2010; 5(1):e8749.

  Pancreatic beta-cells proliferate following administration of the beta-cell toxin streptozotocin. Defining the conditions that promote beta-cell proliferation could benefit patients with diabetes. WePancreatic beta-cells proliferate following administration of the beta-cell toxin streptozotocin. Defining the conditions that promote beta-cell proliferation could benefit patients with diabetes. We have investigated the effect of insulin treatment on pancreatic beta-cell regeneration in streptozotocin-induced diabetic mice, and, in addition, report on a new approach to quantify beta-cell regeneration in vivo. Streptozotocin-induced diabetic were treated with either syngeneic islets transplanted under the kidney capsule or subcutaneous insulin implants. After either 60 or 120 days of insulin treatment, the islet transplant or insulin implant were removed and blood glucose levels monitored for 30 days. The results showed that both islet transplants and insulin implants restored normoglycemia in the 60 and 120 day treated animals. However, only the 120-day islet and insulin implant groups maintained euglycemia (<200 mg/dl) following discontinuation of insulin treatment. The beta-cell was significantly increased in all the 120 day insulin-treated groups (insulin implant, 0.69+/-0.23 mg; and islet transplant, 0.91+/-0.23 mg) compared non-diabetic control mice (1.54+/-0.25 mg). We also show that we can use bioluminescent imaging to monitor beta-cell regeneration in living MIP-luc transgenic mice. The results show that insulin treatment can promote beta-cell regeneration. Moreover, the extent of restoration of beta-cell function and mass depend on the length of treatment period and overall level of glycemic control with better control being associated with improved recovery. Finally, real-time bioluminescent imaging can be used to monitor beta-cell recovery in living MIP-luc transgenic mice.

• In vitro processing and secretion of mutant insulin proteins that cause permanent neonatal diabetes.

  Authors: Sindhu Rajan, Stefani C Eames, Soo-Young Park, Christine Labno, Graeme I Bell, Victoria Prince, Louis H Philipson

  American journal of physiology. Endocrinology and metabolism. 12/2009;

  Permanent neonatal diabetes mellitus is a rare form of insulin-requiring diabetes presenting within the first few weeks or months of life. Mutations in the insulin gene are the second most commonPermanent neonatal diabetes mellitus is a rare form of insulin-requiring diabetes presenting within the first few weeks or months of life. Mutations in the insulin gene are the second most common cause of this form of diabetes. These mutations are located in critical regions of preproinsulin and are likely to prevent normal processing or folding of the preproinsulin/proinsulin molecule. To characterize these mutations, we transiently expressed proinsulin-GFP fusion proteins in MIN6 mouse insulinoma cells. Our study revealed three groups of mutant proteins: (A) mutations that result in retention of proinsulin in the ER and attenuation of secretion of co-transfected wild-type insulin: C43G, F48C and C96Y; (B) mutations with partial ER retention, partial recruitment to granules, and attenuation of secretion of wild-type insulin: G32R, G32S, G47V, G90C and Y108C; and (C), which is similar to (B), but with no significant attenuation of wild-type insulin secretion: A24D and R89C. The mutant insulin proteins do not prevent targeting of wild-type insulin to secretory granules but most appear to lead to decreased secretion of wild-type insulin. Each of the mutants triggers the expression of the pro-apoptotic gene Chop indicating the presence of ER stress.

• TCF7L2 Variant rs7903146 Affects the Risk of Type 2 Diabetes by Modulating Incretin Action.

  Authors: Dennis T Villareal, Heather Robertson, Graeme I Bell, Bruce W Patterson, Hung Tran, Burton Wice, Kenneth S Polonsky

  Diabetes. 11/2009;

  Background. Common variants in the gene TCF7L2 confer the largest effect on the risk of T2D. The present study was undertaken to increase our understanding of the mechanisms by which this geneBackground. Common variants in the gene TCF7L2 confer the largest effect on the risk of T2D. The present study was undertaken to increase our understanding of the mechanisms by which this gene affects T2D risk. Research methods. Eight subjects with risk-conferring TCF7L2 genotypes (TT or TC at rs7903146) and ten-matched subjects with wild-type genotype (CC) underwent 5-h oral glucose tolerance test (OGTT), isoglycemic intravenous glucose infusion, and graded glucose infusion (GGI). Mathematical modeling was used to quantify insulin-secretory profiles during OGTT and glucose infusion protocols. The incretin effect was assessed from ratios of the insulin secretory rates (ISR) during oral and isoglycemic glucose infusions. Dose-response curves relating insulin secretion to glucose concentrations were derived from the GGI. Results. beta-cell responsivity to oral glucose was 50% lower (47+/-4 vs. 95+/-15x10(9) min(-1); P=0.01) in the group of subjects with risk-conferring TCF7L2 genotypes compared with controls. The incretin effect was also reduced by 30% (32+/-4 vs. 46+/-4%; P=0.02) in the at-risk group. The lower incretin effect occurred despite similar GIP and GLP-1 responses to oral glucose. The ISR response over a physiologic glucose concentration range (5-9 mmol/L) was similar between groups. Conclusions. The TCF7L2 variant rs7903146 appears to affect risk of T2D, at least in part, by modifying the effect of incretins on insulin secretion. This is not due to reduced secretion of GLP-1 and GIP but rather due to the effect of TCF7L2 on the sensitivity of the beta-cell to incretins. Treatments that increase incretin sensitivity may decrease the risk of T2D.

• Variation in the perilipin gene (PLIN) affects glucose and lipid metabolism in non-Hispanic white women with and without polycystic ovary syndrome.

  Authors: Toshihide Kawai, Maggie C Y Ng, M Geoffrey Hayes, Issei Yoshiuchi, Takafumi Tsuchiya, Heather Robertson, Nancy J Cox, Kenneth S Polonsky, Graeme I Bell, David A Ehrmann

  Diabetes research and clinical practice. 09/2009;

  Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women. It is characterized by chronic anovulation, hyperandrogenism, obesity and a predisposition to type 2 diabetesPolycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women. It is characterized by chronic anovulation, hyperandrogenism, obesity and a predisposition to type 2 diabetes mellitus (T2DM). Since obesity plays an important role in the etiology of PCOS, we sought to determine if variants in the perilipin gene (PLIN), a gene previously implicated in the development of obesity, were also associated with PCOS. We typed six single nucleotide polymorphisms (haplotype tagging and/or previously associated with obesity or related metabolic traits) in PLIN in 305 unrelated non-Hispanic white women (185 with PCOS and 120 without PCOS). None of the variants was associated with PCOS (P<0.05). However, the variant rs1052700*A was associated with increased risk for glucose intolerance (impaired glucose tolerance or T2DM) in both non-PCOS (OR=1.75 [1.02-3.01], P=0.044) and PCOS subjects (OR=1.67 [1.08-2.59], P=0.022). It was also associated with increased LDL (P=0.007) and total cholesterol levels (P=0.042). These results suggest that genetic variation in PLIN may affect glucose and lipid metabolism in women both with and without PCOS.

• Kir6.2 variant E23K increases ATP-sensitive potassium channel activity and is associated with impaired insulin release and enhanced insulin sensitivity in adults with normal glucose tolerance.

  Authors: Dennis T Villareal, Joseph C Koster, Heather Robertson, Alejandro Akrouh, Kazuaki Miyake, Graeme I Bell, Bruce W Patterson, Colin G Nichols, Kenneth S Polonsky

  Diabetes. 07/2009;

  Background. The E23K variant in the Kir6.2 subunit of the ATP-sensitive potassium (K(ATP)) channel is associated with increased risk of type-2 diabetes (T2D). The present study was undertaken toBackground. The E23K variant in the Kir6.2 subunit of the ATP-sensitive potassium (K(ATP)) channel is associated with increased risk of type-2 diabetes (T2D). The present study was undertaken to increase our understanding of the mechanisms responsible. To avoid confounding effects of hyperglycemia, insulin secretion and action were studied in subjects with the variant who had normal glucose tolerance. Research design and methods. Nine subjects with the E23K genotype K/K and nine matched subjects with the E/E genotype underwent 5-h oral glucose tolerance test (OGTT), graded glucose infusion, and hyperinsulinemic-euglycemic clamp with stable-isotope-labeled tracer infusions to assess insulin secretion, action, and clearance. 461 volunteers consecutively genotyped for the E23K variant also underwent OGTT. Functional studies of the wild-type and E23K variant potassium channels were conducted. Results. Insulin secretory responses to oral and intravenous glucose were reduced by approximately 40% in glucose-tolerant subjects homozygous for E23K. Normal glucose tolerance with reduced insulin secretion suggests a change in insulin sensitivity. The euglycemic-hyperinsulinemic clamp revealed that hepatic insulin sensitivity is approximately 40% greater in subjects with the E23K variant and these subjects demonstrate increased insulin sensitivity after oral glucose. The reconstituted E23K channels confirm reduced sensitivity to inhibitory ATP and increase in open probability, a direct molecular explanation for reduced insulin secretion. Conclusions. The E23K variant leads to overactivity of the K(ATP) channel, resulting in reduced insulin secretion. Initially insulin sensitivity is enhanced thereby maintaining normal glucose tolerance. Presumably over time as insulin secretion falls further or insulin resistance develops, glucose levels rise resulting in T2D.