Effect of autoimmunity risk loci on the honeymoon phase in type 1 diabetes.

OBJECTIVE: To analyze the correlation between duration and depth of honeymoon phase in patients with type 1 diabetes (T1DM) and autoimmunity risk loci. METHODS: From a database of 567 individuals with clinical data, we selected 210 patients for whom we had dense genotyping results of single-nucleotide polymorphisms (SNPs) from our previous genome-wide association studies (GWAS) or targeted genotyping data. Using PLINK software, we analyzed the association between time spent in honeymoon phase as our quantitative trait, and 24 known autoimmunity predisposing SNPs. RESULTS: We found one allele on chromosome 5, rs4613763 mapping to a Prostaglandin Receptor EP4 (PTGER4) to reach statistical significance (P = .0067), in determining a larger proportion of T1DM patients with a detectable honeymoon phase. This polymorphism determines risk for inflammatory bowel disease (IBD) but not T1DM. CONCLUSION: By showing the role of PTGER4 in autoimmune diseases and its effect on inflammatory responses via its interaction with NF-kB, we hypothesize that PTGER4 modulates honeymoon phase in patients with T1DM without influencing the risk of developing T1DM. We hypothesize that this quantitative trait locus promotes inflammatory suppression of beta cells without directly promoting beta-cell destruction. Understanding SNPs that effect function can provide insight in to pathogenesis of T1DM and the mechanism of the honeymoon phase. Because this is a hypothesis-generating study, it needs to be replicated in an additional larger cohort.

Audit of Atypical Femoral Fractures and a Description of Some of Their Features.

PURPOSE: Atypical femoral fractures (AFF) are recently described events related to osteoporosis and, potentially, a rare result of antiresorptive treatment. METHODS: We set out to audit the diagnosis of AFF in an acute hospital. Charts and radiographs were reviewed retrospectively from patients diagnosed with subtrochanteric femoral fractures according to hospital discharge coding at Vancouver General Hospital (VGH), Canada, from January 2005 to March 2013. RESULTS: A total of 3084 patients were discharged from the hospital with a diagnosis of hip fracture between 2005 and 2013. Of these, 204 were coded as having had subtrochanteric fractures; 178 of the patients thus coded had radiographic evidence of other fracture types-usually intertrochanteric fractures. Eleven patients did not have available radiographs. Of the remaining 193 patients whose radiographs were reviewed, 24 (12.4%) fulfilled the published criteria for AFF. OUR OBSERVATIONS WERE: 1) laterality: 13 of 24 AFF (54.2%) were right-sided; 2) there was only one incomplete AFF in this series: a completed fracture was an inclusion criterion, but 1 patient with an AFF had both that fracture and an incomplete fracture and further foci of periosteal or endosteal foci of new bone (PENB) involving the contralateral femur; 3) radiologists had only diagnosed AFF in only 1 of the 24 patients with characteristic radiographic signs of AFF; 4) all but 1 patient had a focus of periosteal and/or endosteal new bone (PENB) through which the fracture line invariably passed, and in the 1 exception the radiography was too poor to be sure of this but there was a symmetrical contralateral focus of PENB; 5) in 19 of 24 patients there was an adequate image of part of the contralateral femur and of these 12 (63%) had a contralateral focus of PENB situated ±2.5 cm from the index lesion site when measured from the upper aspect of the greater trochanter, and in another patient a prior fracture of the contralateral femur had been treated surgically and it was at a symmetrical contralateral location from the index fracture.; 6) in 3 of the 19 patients multiple foci of PENB were detected on the lateral aspect of the contralateral femur even though the examination was of limited extent; and 7) AFFs were associated with bisphosphonate medication in 75% of the patients studied. CONCLUSIONS: Hospital discharge coding misclassified a great majority of femoral fractures as subtrochanteric. As an essential criteria for diagnosing AFF is their subtrochanteric location, this misclassification impaired our ability to retrospectively search for AFF patients. Radiologists tended not to report AFF when typical radiographic characteristics were present. Bilateral and multifocal disease is of interest in pointing to the diagnosis and in suggesting that the mechanism of injury in respect of these unusual fractures is more complex than simple low-energy trauma.

Mechanisms of action of islet neogenesis-associated protein: comparison of the full-length recombinant protein and a bioactive peptide.

Islet neogenesis-associated protein (INGAP) was discovered in the partially duct-obstructed hamster pancreas as a factor inducing formation of new duct-associated islets. A bioactive portion of INGAP, INGAP(104-118) peptide (INGAP-P), has been shown to have neogenic and insulin-potentiating activity in numerous studies, including recent phase 2 clinical trials that demonstrated improved glucose homeostasis in both type 1 and type 2 diabetic patients. Aiming to improve INGAP-P efficacy and to understand its mechanism of action, we cloned the full-length protein (rINGAP) and compared the signaling events induced by the protein and the peptide in RIN-m5F cells that respond to INGAP with an increase in proliferation. Here, we show that, although both rINGAP and INGAP-P signal via the Ras/Raf/ERK pathway, rINGAP is at least 100 times more efficient on a molar basis than INGAP-P. For either ligand, ERK1/2 activation appears to be pertussis toxin sensitive, suggesting involvement of a G protein-coupled receptor(s). However, there are clear differences between the peptide and the protein in interactions with the cell surface and in the downstream signaling. We demonstrate that fluorescent-labeled rINGAP is characterized by clustering on the membrane and by slow internalization (≤5 h), whereas INGAP-P does not cluster and is internalized within minutes. Signaling by rINGAP appears to involve Src, in contrast to INGAP-P, which appears to activate Akt in addition to the Ras/Raf/ERK1/2 pathway. Thus our data suggest that interactions of INGAP with the cell surface are important to consider for further development of INGAP as a pharmacotherapy for diabetes.

A Case Report of Dramatically Increased Thyroglobulin after Lymph Node Biopsy in Thyroid Carcinoma after Total Thyroidectomy and Radioiodine.

Thyroglobulin (Tg) is an important modality for monitoring patients with thyroid cancers, especially after thyroidectomy followed by radioiodine (RAI). It is also used as a marker for burden of thyroid tissue whether malignant or benign. Although there have been several reports of rising serum Tg transiently after thyroid biopsy in intact glands and following palpation or trauma, there are no reports in the literature of elevation in Tg after biopsy of suspicious lesions in thyroidectomized patients. In this paper we report a fascinating case of a considerable and initially worrying, although ultimately transient, rise in Tg in a patient 2 years after total thyroidectomy and RAI ablation after fine needle aspiration (FNA) of a suspicious thyroid bed nodule that was proven positive.

Intentional hypoglycemia to control bingeing in a patient with type 1 diabetes and bulimia nervosa.

Most cases of eating disorders associated with type 1 diabetes mellitus are categorized as diabulimia, a disorder of withholding insulin treatment to lose weight through sustained hyperglycemia. In this paper, we report a unique case of a patient with both type 1 diabetes and bulimia nervosa who has an atypical way of controlling her bingeing by keeping her blood sugars low. This pattern of intentionally sustained hypoglycemia has not been previously described in the literature to the best of our knowledge. Knowing various presentations of eating disorders in patients with type 1 diabetes can provide healthcare workers with enhanced ability in recognizing and educating at-risk patients, in the hope of preventing serious hypoglycemia or complications. Furthermore, a patient's awareness of complications associated with suboptimal control of diabetes, whether by overdosing or underdosing their insulin regimen, might lead to avoidance of disordered eating behaviours.

The effect of type 2 diabetes risk loci on insulin requirements in type 1 diabetes.

OBJECTIVE: To analyze the correlation between insulin requirements of type 1 diabetic (T1D) patients and genotype at type 2 diabetes (T2D) risk loci, obtained in our genome-wide association study. METHODS: From a database of detailed insulin dosing of 567 patients, we selected 177 for whom we also had genome-wide genotyping data. Using PLINK software, we examined the association between insulin requirement as a quantitative trait and nineteen T2D risk loci. RESULTS: Out of 19 single-nucleotide polymorphisms (SNPs), rs13266634 on chromosome 8 and rs7901695 on chromosome 10 showed nominal significance of association (p < 0.05). The first SNP is nonsynonymous (325 Arg>Trp) and maps to the SLC30A8 gene encoding the ß-cell-specific ZnT8 zinc transporter, while the second is an intronic SNP in TCF7L2, the strongest known T2D association. Both loci exert their effect on ß-cells and, in both, the T2D risk allele is associated with lower insulin requirements. CONCLUSION: We identified two T2D susceptibility loci that modulate insulin requirements in T1D patients. Our results are consistent with the association of lower insulin secretion with higher insulin sensitivity. To explain the continuation of this correlation after ß-cell destruction, we hypothesize an epigenetic mechanism that alters insulin responsiveness in T1D patients based on ß-cell function in early life. Such knowledge may allow a more precise approach to treatment.

{beta}-Cell mass dynamics and islet cell plasticity in human type 2 diabetes.

Studies of long-standing type 2 diabetes (T2D) report a deficit in beta-cell mass due to increased apoptosis, whereas neogenesis and replication are unaffected. It is unclear whether these changes are a cause or a consequence of T2D. Moreover, whereas islet morphogenetic plasticity has been demonstrated in vitro, the in situ plasticity of islets, as well as the effect of T2D on endocrine differentiation, is unknown. We compared beta-cell volume, neogenesis, replication, and apoptosis in pancreata from lean and obese (body mass index > or = 27 kg/m(2)) diabetic (5 +/- 2 yr since diagnosis) and nondiabetic cadaveric donors. We also subjected isolated islets from diabetic (3 +/- 1 yr since diagnosis) and nondiabetic donors to an established in vitro model of islet plasticity. Differences in beta-cell volume between diabetic and nondiabetic donors were consistently less pronounced than those reported in long-standing T2D. A compensatory increase in beta-cell neogenesis appeared to mediate this effect. Studies of induced plasticity indicated that islets from diabetic donors were capable of epithelial dedifferentiation but did not demonstrate regenerative potential, as was seen in islets from nondiabetic donors. This deficiency was associated with the overexpression of Notch signaling molecules and a decreased neurogenin-3(+) cell frequency. One interpretation of these results would be that decreased beta-cell volume is a consequence, not a cause, of T2D, mediated by increased apoptosis and attenuated beta-cell (re)generation. However, other explanations are also possible. It remains to be seen whether the morphogenetic plasticity of human islets, deficient in vitro in islets from diabetic donors, is a component of normal beta-cell mass dynamics.