Hypercalcemia of Malignancy: Simultaneous Elevation in Parathyroid Hormone-Related Peptide and 1,25 Dihydroxyvitamin D in Sarcoma.

OBJECTIVE: Hypercalcemia is a common finding in patients who have an underlying malignancy. Only a few cases of hypercalcemia of malignancy have been linked to more than one mechanism of hypercalcemia. Here, we present a patient with liposarcoma and hypercalcemia of malignancy in the setting of simultaneous elevations in parathyroid hormone-related peptide (PTHrP) and 1,25 dihydroxyvitamin D [1,25(OH)2D] levels. Sarcoma-associated hypercalcemia is a rare disorder. METHODS: The patient was an 89-year-old woman with sarcoma-associated hypercalcemia. Multiple mechanisms were uncovered, and treatments were adjusted for them. Literature search for hypercalcemia of malignancy with multiple mechanisms was conducted. RESULTS: This is the first report describing dual mechanisms of sarcoma-associated hypercalcemia and only the fifth report on PTHrP and 1,25(OH)2D simultaneously causing hypercalcemia of malignancy. CONCLUSION: Based on this finding, we recommend measuring the 1,25(OH)2D levels in conjunction with the PTHrP level in patients with malignancy as this would allow for a more proactive approach to the diagnosis and treatment of hypercalcemia of malignancy.

Atezolizumab-induced type 1 diabetes mellitus in a patient with metastatic renal cell carcinoma.

Checkpoint inhibitor immunotherapy has revolutionised cancer treatment since its inception. During an inflammatory response, activated cytotoxic T cells expressing programmed cell death protein 1 (PD-1) interact with programmed cell death-ligand 1 (PD-L1) on peripheral tissues to thwart an autoimmune reaction. Cancer cells upregulate PD-L1 expression to evade the immune system and are vulnerable to attack in the presence of PD-1 or PD-L1 checkpoint inhibitors. However, blockade of this pathway also contributes to the unintended side effect of autoimmune endocrinopathies. Atezolizumab, a checkpoint inhibitor against PD-L1, is associated with the rare complication of type 1 diabetes. We present a case of glutamic acid decarboxylase antibody-positive type 1 diabetes developing in a patient with a long-standing history of well-controlled type 2 diabetes following treatment with atezolizumab for metastatic renal cell carcinoma.

Thyroid Storm with Multiorgan Failure Treated with Plasmapheresis.

BACKGROUND: Thyroid storm is a severe manifestation of thyrotoxicosis and can present with multiorgan failure. First line treatment of thyroid storm is directed towards decreasing thyroid hormone production and peripheral conversion of T4 to T3, and treating adrenergic symptoms. When medical therapy fails, plasmapheresis is an alternative treatment option. Here we present a patient with thyroid storm and multiorgan failure who was treated with plasmapheresis. CASE: A 50-year-old male with a history of hyperthyroidism, hypertension, and congestive heart failure presented to another hospital with fever and altered mentation. He was found to have pneumonia on imaging and was started on antibiotics. He developed shock complicated by atrial fibrillation with rapid ventricular rate which was treated with amiodarone. He was transferred to our hospital for further management. On arrival, TSH was <0.01 mIU/L, free T4 was >7 ng/dL and total T3 was 358 ng/dL. The endocrinology team determined he was in thyroid storm. His medical treatment of thyroid storm was aggressively titrated to maximal therapy. His hospital course was complicated by transaminitis, respiratory failure requiring intubation, shock requiring vasopressor support, kidney failure requiring continuous renal replacement therapy, and heart failure. Despite maximal anti-thyroid therapy, he had not improved clinically and T4 and T3 remained markedly elevated. A 4-day course of plasmapheresis was initiated resulting in marked lowering of T4 and T3 and clinical stability. CONCLUSION: While current guidelines for plasmapheresis for thyroid storm recommend individualized decision making, no further clarification is provided on who would be a good candidate for the procedure. We present a patient with thyroid storm and multiorgan failure who was treated with plasmapheresis after failing maximal medical therapy. Given the significant improvement seen with plasmapheresis, endocrinologists should consider this mode of treatment earlier in the course of thyroid storm when patients are not improving with medical therapy alone.

Severe hypercalcaemia due to household cleaner ingestion.

We report the case of a 59-year-old man with a history of type 2 diabetes, hypertension and chronic kidney disease who presented with symptomatic severe hypercalcaemia (calcium 15.8 mg/dL) and acute kidney injury. Evaluation revealed that the hypercalcaemia was not mediated by parathyroid hormone (PTH), PTH-related peptide or 1,25-hydroxyvitamin D. Adrenal insufficiency was subsequently diagnosed and was initially thought to be the aetiology of the hypercalcaemia. He was treated with intravenous fluid, pamidronate and started on hydrocortisone with resolution of his hypercalcaemia. Over the next several months, despite adherence to hydrocortisone therapy, the patient continued to have recurrent severe hypercalcaemia requiring hospitalisation. Additional laboratory evaluation showed similar results to the initial evaluation. On further questioning, the patient admitted to routinely ingesting the household cleaning product Comet, which contains a large amount of calcium. Psychiatric assessment confirmed the diagnosis of pica. The patient eventually discontinued ingestion of Comet with resolution of his hypercalcaemia.

CYSTIC PROLACTINOMA: A SURGICAL DISEASE?

OBJECTIVE: Since the advent of dopamine agonists, prolactinomas have been primarily treated medically. However, studies show conflicting data on whether these agents are as effective as surgery for predominantly cystic prolactinomas. We present a case of a patient with a cystic prolactinoma for which surgery was selected as first-line therapy. METHODS: Literature review. RESULTS: A 26-year-old African American man presented to an outside hospital with complaints of dull right-sided headaches for 1 week. The headache worsened over the next few days, which prompted him to go to the emergency room. The evaluation included a head computed tomography, which demonstrated a 4-cm solid/cystic pituitary mass with possible hemorrhagic conversion and compression of the optic chiasm. He was transferred to University of Maryland Medical Center for neurosurgical evaluation. He denied symptoms of pituitary hormone excess or deficiency. He denied visual symptoms, though formal visual field testing demonstrated temporal hemianopia. Hormonal evaluation revealed hyperprolactinemia (prolactin, 1,627 ng/mL) and central hypothyroidism (thyroid-stimulating hormone, 2.72 µIU/mL; free thyroxine, 0.5 ng/dL). Because of the large cystic component of the prolactinoma and clinical evidence for compression of the optic chiasm, the patient underwent transsphenoidal resection of the mass. Postoperatively, the patient was started on bromocriptine for suppression of residual prolactinoma tissue. Notably, the patient developed several complications postoperatively, including diabetes insipidus and secondary hypogonadism. CONCLUSION: Initial management strategies for cystic prolactinomas have been debated. This case highlights the importance of careful consideration of both medical and surgical treatment options in patients with prolactinomas with large cystic components.

Non-uraemic calciphylaxis (NUC) postliver transplantation.

Calciphylaxis is a rare and life-threatening disease characterized by cutaneous arteriolar stenosis and vascular thrombosis leading to skin ischaemia and necrosis. While calciphylaxis occurs mostly in patients with end-stage renal disease, the disorder has been described in patients with normal renal function, namely non-uraemic calciphylaxis (NUC). A 41-year-old African-American woman presented with a painful ulcerative rash on her thighs and right buttock 2 months after undergoing an orthotopic liver transplantation. She underwent debridement of the lesions and an excisional biopsy of one of the lesions, which revealed calciphylaxis. She was treated with sodium thiosulfate, cinacalcet and hyperbaric oxygen with complete resolution of the lesions 4-5 months after presentation. While she was treated with a course of high-dose glucocorticoids after the transplant, she did not have other risk factors for calciphylaxis. NUC should be considered in the differential diagnosis of necrotic skin lesions in postliver transplant patients.

Insulin Pump and Continuous Glucose Monitor Initiation in Hospitalized Patients with Type 2 Diabetes Mellitus.

BACKGROUND: Insulin pumps and continuous glucose monitoring (CGM) are commonly used by patients with diabetes mellitus in the outpatient setting. The efficacy and safety of initiating inpatient insulin pumps and CGM in the nonintensive care unit setting is unknown. MATERIALS AND METHODS: In a prospective pilot study, inpatients with type 2 diabetes were randomized to receive standard subcutaneous basal-bolus insulin and blinded CGM (group 1, n = 5), insulin pump and blinded CGM (group 2, n = 6), or insulin pump and nonblinded CGM (group 3, n = 5). Feasibility, glycemic control, and patient satisfaction were evaluated among groups. RESULTS: Group 1 had lower mean capillary glucose levels, 144.5 ± 19.5 mg/dL, compared with groups 2 and 3, 191.5 ± 52.3 and 182.7 ± 59.9 mg/dL (P1 vs. 2+3 = 0.05). CGM detected 19 hypoglycemic episodes (glucose <70 mg/dL) among all treatment groups, compared with 12 episodes detected by capillary testing, although not statistically significant. No significant differences were found for the total daily dose of insulin or percentage of time spent below target glucose range (<90 mg/dL), in target glucose range (90-180 mg/dL), or above target glucose range (>180 mg/dL). On the Diabetes Treatment Satisfaction Questionnaire-Change, group 3 reported increased hyperglycemia and decreased hypoglycemia frequency compared with the other two groups, although the differences did not reach statistical significance. CONCLUSIONS: Insulin pump and CGM initiation are feasible during hospitalization, although they are labor intensive. Although insulin pump initiation may not lead to improved glycemic control, there is a trend toward CGM detecting a greater number of hypoglycemic episodes. Larger studies are needed to determine whether use of this technology can lower inpatient morbidity and mortality.

Inpatient Continuous Glucose Monitoring and Glycemic Outcomes.

Continuous glucose monitoring (CGM) is commonly used in the outpatient setting to improve diabetes management. CGM can provide real-time glucose trends, detecting hyperglycemia and hypoglycemia before the onset of clinical symptoms. In 2011, at the time the Endocrine Society CGM guidelines were published, the society did not recommend inpatient CGM as its efficacy and safety were unknown. While many studies have subsequently evaluated inpatient CGM accuracy and reliability, glycemic outcome studies have not been widely published. In the non-ICU setting, investigational CGM studies have commonly blinded providers and patients to glucose data. Retrospective review of the glucose data reflects increased hypoglycemia detection with CGM. In the ICU setting, data are inconsistent whether CGM can improve glycemic outcomes. Studies have not focused on hospitalized patients with type 1 diabetes mellitus, the population most likely to benefit from inpatient CGM. This article reviews inpatient CGM glycemic outcomes in the non-ICU and ICU setting.

Role of glycemic control on hospital-related outcomes in patients with diabetes mellitus undergoing renal transplantation.

OBJECTIVE: To compare length of stay (LOS) and incidence of hypoglycemic events and infections in hospitalized patients with diabetes mellitus (DM) undergoing renal transplantation, among groups of patients defined by admission glucose and mean inpatient daily glucose. METHODS: A retrospective analysis of 190 charts of patients with DM who underwent renal transplantation over a 2-year period was conducted. Patients were grouped according to admission glucose and mean inpatient daily glucose (≤140 mg/dL, 141-180 mg/dL, and >180 mg/dL). RESULTS: Admission glucose was not associated with LOS. A mean inpatient daily glucose of ≤140 mg/dL was associated with a longer LOS compared to a mean inpatient daily glucose of >180 mg/dL (p=0.03). Patients with an admission glucose of ≤140 mg/dL had approximately half the rate of hypoglycemic events compared to those with admission glucose of 141-180 mg/dL (odds ratio [OR]=2.1; p=0.02) or >180 mg/dL (OR=1.9; p=0.04). However, patients whose mean daily glucose was ≤140 mg/dL had approximately twice the rate of hypoglycemic events than those whose mean daily glucose was 141-180 mg/dL (OR=0.4; p=0.01) or >180 mg/dL (OR=0.4; p=0.004). The incidence of infections was low and was not associated with admission or mean daily glucose levels. CONCLUSION: Lower mean daily inpatient glucose levels (≤140 mg/dL) are associated with longer LOS and greater incidence of hypoglycemic episodes in diabetes patients undergoing renal transplantation. Our findings suggest that target blood glucose levels of 140-180 mg/dL may be appropriate in this specific population. Additional prospective research is needed to confirm these findings.

Patient-Centered Personal Health Record and Portal Implementation Toolkit for Ambulatory Clinics: A Feasibility Study.

Personal health records and patient portals have been shown to be effective in managing chronic illnesses. Despite recent nationwide implementation efforts, the personal health record and patient portal adoption rates among patients are low, and the lack of support for patients using the programs remains a critical gap in most implementation processes. In this study, we implemented the Patient-Centered Personal Health Record and Patient Portal Implementation Toolkit in a large diabetes/endocrinology center and assessed its preliminary impact on personal health record and patient portal knowledge, self-efficacy, patient-provider communication, and adherence to treatment plans. Patient-Centered Personal Health Record and Patient Portal Implementation Toolkit is composed of Patient-Centered Personal Health Record and Patient Portal Implementation Toolkit-General, clinic-level resources for clinicians, staff, and patients, and Patient-Centered Personal Health Record and Patient Portal Implementation Toolkit Plus, an optional 4-week online resource program for patients ("MyHealthPortal"). First, Patient-Centered Personal Health Record and Patient Portal Implementation Toolkit-General was implemented, and all clinicians and staff were educated about the center's personal health record and patient portal. Then general patient education was initiated, while a randomized controlled trial was conducted to test the preliminary effects of "MyHealthPortal" using a small sample (n = 74) with three observations (baseline and 4 and 12 weeks). The intervention group showed significantly greater improvement than the control group in patient-provider communication at 4 weeks (t56 = 3.00, P = .004). For other variables, the intervention group tended to show greater improvement; however, the differences were not significant. In this preliminary study, Patient-Centered Personal Health Record and Patient Portal Implementation Toolkit showed potential for filling the gap in the current personal health record and patient portal implementation process. Further studies are needed using larger samples in other settings to ascertain if these results are generalizable to other populations.

Arsenic exposure is associated with diminished insulin sensitivity in non-diabetic Amish adults.

BACKGROUND: Substantial evidence supports an association between diabetes and arsenic at high exposure levels, but results are mixed at low exposure levels. The aetiology of diabetes involves insulin resistance and ß-cell dysfunction. However, only a few epidemiologic studies have examined measures of insulin resistance and ß-cell function in relation to arsenic exposure, and no studies have tested for associations with the oral glucose tolerance test (OGTT). We examined the association between urinary total arsenic and OGTT-based markers of insulin sensitivity and ß-cell function. METHODS: We studied 221 non-diabetic adults (mean age = 52.5 years) from the Amish Family Diabetes Study. We computed OGTT-based validated measures of insulin sensitivity and ß-cell function. Generalized estimating equations accounting for sibship were used to estimate associations. RESULTS: After adjusting for age, sex, waist-to-hip ratio and urinary creatinine, an interquartile range increase in urinary total arsenic (6.24 µg/L) was significantly, inversely associated with two insulin sensitivity measures (Stumvoll metabolic clearance rate = -0.23 mg/(kg min), (95% CI: -0.38, -0.089), p = 0.0015; Stumvoll insulin sensitivity index = -0.0029 µmol/(kg min pM), (95% CI: -0.0047, -0.0011), p = 0.0015). Urinary total arsenic was also significantly associated with higher fasting glucose levels (0.57 mg/dL (95% CI: 0.06, 1.09) per interquartile range increase, p = 0.029). No significant associations were found between urinary total arsenic and ß-cell function measures. CONCLUSIONS: This preliminary study found that urinary total arsenic was associated with insulin sensitivity but not ß-cell function measures, suggesting that low-level arsenic exposure may influence diabetes risk through impairing insulin sensitivity. Copyright © 2015 John Wiley & Sons, Ltd.

Polymorphisms in the SOCS7 gene and glucose homeostasis traits.

BACKGROUND: SOCS7 is a member of the suppressor of cytokine signaling family of proteins and is expressed in skeletal muscle and islets. SOCS7 deficient mice develop islet hyperplasia in the setting of increased insulin sensitivity and normal glucose tolerance. The objective of this study was to determine if variants in SOCS7 play a role in variation of glucose and insulin levels and the development of type 2 diabetes (T2DM). RESULTS: Five SOCS7 tagging SNPs were genotyped in diabetic and nondiabetic Old Order Amish. A case-control study was performed in T2DM (n = 145) and normal glucose tolerant (n = 358) subjects. Nominal associations were observed with T2DM and the minor alleles for rs8068600 (P = 0.01) and rs8074124 (P = 0.04); however, only rs8068600 remained significant after Bonferroni adjustment for multiple comparisons (P = 0.01). Among nondiabetic Amish (n = 765), no significant associations with glucose or insulin traits including fasting or 2 hour glucose and insulin from the oral glucose tolerance test, insulin or glucose area under the curve, Matsuda Index or HOMA-IR were found for any of the SNPs. CONCLUSION: In conclusion, genetic variants in the SOCS7 gene do not impact variation in glucose homeostasis traits and only minimally impact risk of T2DM in the Old Order Amish. Our study was not able to address whether rare variants that potentially impact gene function might influence T2DM risk.

Chronic stress and decreased physical exercise: impact on weight for African American women.

OBJECTIVE: African American women continue to have the highest prevalence of obesity in the United States and in the state of Maryland they are disproportionately affected by overweight and obesity. There are many contributing factors including chronic stress and the use of health behaviors such as physical exercise that play a role in increased weight for African American women. We examined the relationship of stress to weight and the role of physical exercise in African American paraprofessional women. DESIGN: Cross-sectional study SETTING: African American paraprofessionals were asked about their perspectives regarding association with chronic stress and physical exercise. RESULTS: The three most salient stressors for the women were finances (33%), work (28%) and family/friends (19%). Ninety percent of the women were overweight or obese. Significant predictors of increased BMI were lack of physical exercise (P = .004) and health compared to others (P = .006). Ethnic discrimination was a form of chronic stress (r = .319) but was not correlated with BMI (r = .095). Decreased physical exercise (P = .02) mediated the relationship between chronic stress and BMI. CONCLUSION: Findings regarding finance and work stress suggest the need for employers to consider the impact of job strain when implementing employee health programs to decrease stress and improve health. A focus on decreased physical exercise, unhealthy eating habits and misperceptions regarding increased risk for obesity related diseases with health status may be helpful to include in intervention strategies to decrease obesity for this population.

Transmembrane emp24 protein transport domain 6 is selectively expressed in pancreatic islets and implicated in insulin secretion and diabetes.

OBJECTIVES: The objective of the study was to identify pancreatic islet-selective gene(s) that may play a functional role in islet biology and diabetes development. METHODS: Through bioinformatics, we identified and cloned a pancreas-enriched complementary DNA encoding transmembrane emp24 protein transport domain 6 (TMED6) and examined its mRNA and protein expression in tissues and islet cell lines by Northern analysis and immunofluorescence histochemistry. We also studied the role of TMED6 in insulin secretion using a knockdown approach and its gene expression changes during the development of diabetes in Goto-Kakizaki rats. RESULTS: TMED6 is selectively expressed in pancreatic islets and belongs to the EMP24_GP25L superfamily, which is known to be involved in protein trafficking and secretion. Northern analysis revealed that TMED6 mRNA is highly and selectively expressed in pancreas. Immunofluorescence histochemistry of mouse pancreas showed that TMED6 expression is restricted to pancreatic islets with higher levels in α cells than ß cells. Knockdown of TMED6 gene expression in Min6 ß cells decreased insulin secretion. Moreover, TMED6 gene expression was significantly lower in diabetic Goto-Kakizaki rats. CONCLUSIONS: TMED6 may play a functional role in islet biology, particularly in hormone production or secretion, and its dysregulation may be implicated in the development of diabetes.

Computerisation of a paper-based intravenous insulin protocol reduces errors in a prospective crossover simulated tight glycaemic control study.

BACKGROUND: Paper-based continuous intravenous insulin protocols for tight glycaemic control (TGC) are typically complex, error-prone, time-consuming and burdensome. Little is known about the errors that occur as a result of misinterpretation and whether computerised protocols reduce errors. OBJECTIVE: To compare the errors resulting from protocol misinterpretation, time required to manage insulin infusions and nursing satisfaction between a computerised insulin protocol and a paper-based protocol. METHODS: In a crossover study, 62 ICU nurses completed 10 TGC simulated scenarios for the computerised and paper protocols. Scenarios evaluated three phases of insulin management: initiation, titration and transition. Scenarios response errors, time to completion and user satisfaction were examined. RESULTS: A total of 620 responses were recorded using both protocols. The computerised protocols were associated with higher user satisfaction, as well as: fewer errors in the titration (13 vs. 113 errors, p=.0001) and transition phases (9 vs. 23 errors, p=.001), fewer dosing errors, although not statistically significant (p=.096), in the initiation phase, and less time to complete in the titration phase (6 vs. 9.5 min, p=.0001). CONCLUSIONS: In a simulated environment, a computerised protocol for TGC resulted in significant insulin dosing error reduction, saved time and improved nurse satisfaction.

Sequence variation in IGF1R is associated with differences in insulin levels in nondiabetic Old Order Amish.

BACKGROUND: Insulin growth factor-1 receptor (IGF1R) encodes the insulin-like growth factor 1 receptor, a transmembrane tyrosine kinase receptor located on chromosome 15q26.3, in a region of linkage (LOD = 2.53, P = 0.00032) to Insulin30 on an OGTT in the Old Order Amish. Mouse models with beta-cell-specific deficiency of IGF1R demonstrate defects in glucose-stimulated insulin secretion. METHODS: To test the hypothesis that genetic variation in IGF1R is associated with impaired insulin secretion, we genotyped 54 SNPs in 778 nondiabetic subjects from the AFDS who had undergone OGTTs and tested them for association with ln Insulin30 and ISI. RESULTS: No individual SNPs were significantly associated with ln Insulin30 or ISI using a multiple hypothesis testing adjusted P < 0.002. Tests of association of 4-SNP haplotypes constructed by a windowing approach revealed an association of the CTTG-variant of a 4-SNP haplotype found in intron 20 (rs1784195-rs2715439-rs8034284-rs12440962) with lower ISI levels (beta = 0.18, SE(beta) = 0.05, P = 0.001). CONCLUSIONS: Sequence variation in IGF1R may influence insulin secretory function, although further studies in other populations will be needed to confirm these findings.

Variations in the G6PC2/ABCB11 genomic region are associated with fasting glucose levels.

Identifying the genetic variants that regulate fasting glucose concentrations may further our understanding of the pathogenesis of diabetes. We therefore investigated the association of fasting glucose levels with SNPs in 2 genome-wide scans including a total of 5,088 nondiabetic individuals from Finland and Sardinia. We found a significant association between the SNP rs563694 and fasting glucose concentrations (P = 3.5 x 10(-7)). This association was further investigated in an additional 18,436 nondiabetic individuals of mixed European descent from 7 different studies. The combined P value for association in these follow-up samples was 6.9 x 10(-26), and combining results from all studies resulted in an overall P value for association of 6.4 x 10(-33). Across these studies, fasting glucose concentrations increased 0.01-0.16 mM with each copy of the major allele, accounting for approximately 1% of the total variation in fasting glucose. The rs563694 SNP is located between the genes glucose-6-phosphatase catalytic subunit 2 (G6PC2) and ATP-binding cassette, subfamily B (MDR/TAP), member 11 (ABCB11). Our results in combination with data reported in the literature suggest that G6PC2, a glucose-6-phosphatase almost exclusively expressed in pancreatic islet cells, may underlie variation in fasting glucose, though it is possible that ABCB11, which is expressed primarily in liver, may also contribute to such variation.

A genome-wide linkage scan of insulin level derived traits: the Amish Family Diabetes Study.

OBJECTIVE: Serum insulin levels are altered in insulin resistance and insulin deficiency, states that are associated with the development of type 2 diabetes. The goal of our study was to identify chromosomal regions that are likely to harbor genetic determinants of these traits. RESEARCH DESIGN AND METHODS: We conducted a series of genetic analyses, including genome-wide and fine-mapping linkage studies, based on insulin levels measured during an oral glucose tolerance test (OGTT) in 552 nondiabetic participants in the Amish Family Diabetes Study. Indices of insulin secretion included the insulinogenic index and insulin at 30 min postglucose load (insulin 30), while indices of insulin resistance included homeostasis model assessment of insulin resistance (HOMA-IR) and fasting insulin. Insulin area under the curve, a measure of both insulin secretion and insulin resistance, was also examined. RESULTS: All traits were modestly heritable, with heritability estimates ranging from 0.1 to 0.4 (all P < 0.05). There was significant genetic correlation between fasting insulin and HOMA-IR (rho(G) > 0.86, P < 0.05), as well as insulin 30 and insulinogenic index (rho(G) = 0.81, P < 0.0001), suggesting that common genes influence variation in these pairs of traits. Suggestive linkage signals in the genome scan were to insulin 30 on chromosome 15q23 (logarithm of odds [LOD] 2.53, P = 0.00032) and to insulinogenic index on chromosome 2p13 (LOD 2.51, P = 0.00034). Fine-mapping study further refined our signal for insulin 30 on chromosome 15 (LOD 2.38 at 68 cM). CONCLUSIONS: These results suggest that there may be different genes influencing variation in OGTT measures of insulin secretion and insulin resistance.

Polymorphisms in the transcription factor 7-like 2 (TCF7L2) gene are associated with type 2 diabetes in the Amish: replication and evidence for a role in both insulin secretion and insulin resistance.

Transcription factor 7-like 2 (TCF7L2) regulates genes involved in cell proliferation and differentiation. The TCF7L2 gene is located on chromosome 10q25 in a region of replicated linkage to type 2 diabetes. Recently, a microsatellite marker in intron 3 (DG10S478) and five correlated single nucleotide polymorphisms (SNPs) were identified in Icelandic individuals that showed strong association with type 2 diabetes, which was replicated in Danish and European-American cohorts. We genotyped four of the SNPs (rs7901695, rs7903146, rs11196205, and rs12255372) in Amish subjects with type 2 diabetes (n = 137), impaired glucose tolerance (IGT; n = 139), and normal glucose tolerance (NGT; n = 342). We compared genotype frequencies in subjects with type 2 diabetes with those with NGT and found marginal association for rs7901695 (P = 0.05; odds ratio [OR] 1.51); comparison between NGT control subjects and the combined type 2 diabetes/IGT case group showed strong association with rs7901695 and rs7903146 (P = 0.008-0.01; OR 1.53-1.57) and marginal association with rs11196205 and rs12255372 (P = 0.07 and P = 0.04, respectively). In an expanded set of 698 Amish subjects without diabetes, we found no association with insulin and glucose levels during a 3-h oral glucose tolerance test. We also genotyped these SNPs in nondiabetic, non-Amish subjects (n = 48), in whom intravenous glucose tolerance tests were performed, and found an association between rs7901695 and rs7903146 and insulin sensitivity (P = 0.003 and P = 0.005, respectively) and disposition index (P = 0.04 and P = 0.007, respectively). These data provide replicating evidence that variants in TCF7L2 increase the risk for type 2 diabetes and novel evidence that the variants likely influence both insulin secretion and insulin sensitivity.