Airani Sathananthan

Common Genetic Variation in GLP1R and Insulin Secretion in Response to Exogenous GLP-1 in Nondiabetic Subjects: A pilot study

OBJECTIVE Glucagon-like peptide (GLP)-1 receptor is encoded by GLP1R. The effect of genetic variation at this locus on the response to GLP-1 is unknown. This study assessed the effect of GLP1R polymorphisms on insulin secretion in response to hyperglycemia and to infused GLP-1 in nondiabetic subjects. RESEARCH DESIGN AND METHODS Eighty-eight healthy individuals (aged 26.3 ± 0.6 years, fasting glucose 4.83 ± 0.04 mmol/l) were studied using a hyperglycemic clamp. GLP-1 was infused for the last 2 h of the study (0.75 pmol/kg/min over 121–180 min, 1.5 pmol/kg/min over 181–240 min). β-Cell responsivity (ΦTotal) was measured using a C-peptide minimal model. The effect of 21 tag single nucleotide polymorphisms (SNPs) in GLP1R on ΦTotal was examined. RESULTS Two SNPs (rs6923761 and rs3765467) were nominally associated with altered β-cell responsivity in response to GLP-1 infusion. CONCLUSIONS Variation in GLP1R may alter insulin secretion in response to exogenous GLP-1. Future studies will determine whether such variation accounts for interindividual differences in response to GLP-1–based therapy.

Late‐night salivary cortisol for diagnosis of Cushing’s syndrome by liquid chromatography/tandem mass spectrometry assay

Background  Late‐night salivary cortisol (LNSC) measurements have been increasingly used by physicians as an initial diagnostic test for evaluation of patients with clinical suspicion of Cushing’s syndrome (CS). Published studies include various numbers of cases, controls and importantly, various assay methods (vast majority various immunoassays), as well as various methods to generate cut‐points.

Metabolic and target organ outcomes after total pancreatectomy: Mayo Clinic experience and meta-analysis of the literature

Introduction  Total pancreatectomy (TP) has been associated with substantial metabolic abnormalities and poor glycaemic control limiting its use. Because data reported to date are limited, we evaluated outcomes related to the diabetes mellitus obligated by TP.

Diabetes-Associated Common Genetic Variation and Its Association With GLP-1 Concentrations and Response to Exogenous GLP-1

The mechanisms by which common genetic variation predisposes to type 2 diabetes remain unclear. The disease-associated variants in TCF7L2 (rs7903146) and WFS1 (rs10010131) have been shown to affect response to exogenous glucagon-like peptide 1 (GLP-1), while variants in KCNQ1 (rs151290, rs2237892, and rs2237895) alter endogenous GLP-1 secretion. We set out to validate these observations using a model of GLP-1–induced insulin secretion. We studied healthy individuals using a hyperglycemic clamp and GLP-1 infusion. In addition, we measured active and total GLP-1 in response to an oral challenge in nondiabetic subjects. After genotyping the relevant single nucleotide polymorphisms, generalized linear regression models and repeated-measures ANCOVA models incorporating potential confounders, such as age and BMI, were used to assess the associations, if any, of response with genotype. These variants did not alter GLP-1 concentrations in response to oral intake. No effects on β-cell responsiveness to hyperglycemia and GLP-1 infusion were apparent. Diabetes-associated variation (T allele at rs7903146) in TCF7L2 may impair the ability of hyperglycemia to suppress glucagon (45 ± 2 vs. 47 ± 2 vs. 60 ± 5 ng/L for CC, CT, and TT, respectively, P = 0.02). In nondiabetic subjects, diabetes-associated genetic variation does not alter GLP-1 concentrations after an oral challenge or its effect on insulin secretion.

Defects in GLP-1 Response to an Oral Challenge Do Not Play a Significant Role in the Pathogenesis of Prediabetes

CONTEXT There has been much speculation as to whether defects in glucagon-like peptide-1 (GLP-1) secretion play a role in the pathogenesis of type 2 diabetes and the progression from normal glucose tolerance to prediabetes and diabetes. OBJECTIVE Our objective was to determine whether fasting and postchallenge concentrations of active and total GLP-1 decrease as glucose tolerance and insulin secretion worsen across the spectrum of prediabetes. DESIGN This was a cross-sectional study. SETTING The study was performed in the clinical research unit of an academic medical center. PARTICIPANTS Participants included 165 subjects with a fasting glucose below 7.0 mmol/liter and not taking medications known to affect gastrointestinal motility or glucose metabolism. INTERVENTION Intervention included a 2-h, 75-g oral glucose tolerance test with insulin, C-peptide, glucagon, and GLP-1 measurements at seven time points. MAIN OUTCOME MEASURE We evaluated the association of integrated, incremental active, and total GLP-1 concentrations with integrated, incremental glucose response to 75 g oral glucose. RESULTS After accounting for covariates, there was no evidence of a relationship of incremental glucose concentrations after oral glucose tolerance test with active and total GLP-1 (r(s) = -0.16 and P = 0.14, and r(s) = 0.00 and P > 0.9, respectively). There also was no association of GLP-1 concentrations with insulin secretion and action. CONCLUSIONS The lack of association of GLP-1 concentrations with glucose tolerance status and with insulin secretion and action in a cohort encompassing the full spectrum of prediabetes strongly argues against a significant contribution of defects in GLP-1 secretion to the pathogenesis of prediabetes.

A concerted decline in insulin secretion and action occurs across the spectrum of fasting and postchallenge glucose concentrations.

Aims/hypothesis  Individuals with impaired fasting glucose (IFG) are at increased risk of developing diabetes over the subsequent decade. However, there is uncertainty as to the mechanisms contributing to the development of diabetes. We sought to quantitate insulin secretion and action across the prediabetic range of fasting glucose.

Can sorafenib cause hypothyroidism

Sunitinib, a multiple tyrosine kinase inhibitor with antiangiogenic properties has been reported to be associated with hypothyroidism in 57-85% of treated patients, though the mechanism is unclear 13. Sunitinib and imatinib have even been reported to cause hypothyroidism in patients already on replacement levothyroxine for prior thyroidectomy 4,5. We report a 53-year-old woman with non-functional metastatic islet cell carcinoma treated with sorafenib, a novel multiple tyrosine kinase inhibitor, in the context of a IRB-approved clinical trial (MC044H), with resultant development of hypothyroidism. Our patient initially presented to our institution with a sudden exacerbation of a chronic non-specific epigastric pain. She was found to have metastatic pancreatic islet cell carcinoma with liver metastases. Due to lack of symptoms, she was observed for three years prior to initiation of therapy, which was done due to slow progression. She initially received gefitinib in a clinical trial, but progressed after 6 months. She subsequently enrolled in the trial using sorafenib (400 mg twice daily). The dose was reduced to 200 mg po BID due to epigastric discomfort. After one month at the reduced dose, she developed transient throat pain, followed by heat intolerance, palpitations and hair loss. Her thyroid stimulating hormone (TSH) level was suppressed to 0.02 mIU/L (0.3-5.0, see Table 1) One month later, the TSH was repeated and a total thyroxine checked, which was slightly elevated (though the patient was on estrogen replacement which can elevate total thyroxine levels 6). The only prior baseline value was a TSH of 2.6 mIU/L, drawn three years earlier. For the palpitations, she was placed on Journal of Chemotherapy Vol. 19 n. 3 (352-353) 2007