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Effect of Autoimmunity Risk Loci on the Honeymoon Phase in Type 1 Diabetes
Abstracts / Can J Diabetes 39 (2015) 529e547
536
025-2015.
GLUCOSE AND METABOLISM
A Case of Marked Insulin Resistance in a Type 1 Diabetic Patient ALLISON MARTIN*, KIRAN WAQAS Prince Albert, SK Insulin resistance which is not a typical feature of Type 1 diabetes may lead to poor glycemic control and increased risk for microvascular and macrovascular complications. These patients may develop anti-insulin antibodies from previous exposure to animal insulin. Other risk factors for developing anti insulin antibodies include asthma, history of allergies and autoimmunity, These antibodies may act as an antagonist or agonist to the insulin receptor resulting in hyperglycemia or hypoglycemia respectively. We studied a 24 year old Caucasian female with type 1 diabetes diagnosed in 2002. She was referred by her family doctor to the endocrine clinic in June 2014. She reported multiple episodes of hyperglycemia and hypoglycemia and being treated with a continuous subcutaneous insulin infusion of Humalog since 2009. She was requiring 126 units of insulin/day. Her HbA1c was 9.7 % (percent). Her past medical history include asthma, multiple allergies, benign brain tumor and autoimmune thyroid disease. She was previously exposed to animal insulin and was on the oral contraceptive pill. Her family history is significant for autoimmune disorders. Her immunochemistry showed positive anti-glutamic acid decarboxylase (GAD) antibodies and anti-insulin antibodies. We substituted insulin aspart (Novorapid) for Humalog in September 2014. She required less insulin and and her glycemic control improved significantly. Her HbA1c went down by 1.8 % over a period of 6 months. In conclusion, insulin resistance should be considered in Type 1 diabetic patients requiring high doses of insulin with persistently poor glycemic control with no obvious cause. In this case, the patient was not responding to insulin therapy despite good compliance with her diabetes management. We believe she developed some resistance to Humalog which is a human insulin possibly due to blocking antibodies. It is important to recognize this possible complication of insulin therapy and treatment should include a trial of another brand of insulin.
026-2015.
REPRODUCTIVE ENDOCRINOLOGY
Attitudes, Knowledge and Beliefs Regarding Fertility Preservation Among People of Transgendered Experience: Preliminary Results ADAM MILLAR*, BRIAN H.K. KIM, DANA LIVNE-SEGEV, RAY FUNG, KEITH JARVI, ADAM C. MILLAR Toronto, ON The transgendered population has traditionally been excluded from population health and sexuality research. Limited research suggests that many transgendered people have not considered fertility preservation. Modern techniques allow for people of transgender experience to have biological children through cryopreservation of sperm or eggs. It is believed that multiple barriers prevent people of transgender experience from engaging in fertility preservation. This ongoing study examines the attitudes, knowledge and beliefs of people of transgendered experience in regards to fertility. Patients at different stages of transition were sampled from multiple endocrine, psychiatric and family practice clinics in Toronto. Semi-structured questionnaires were distributed during routine medical appointments. The target sample size for this study is 200 patients, making this the largest study to date that will specifically evaluate reproductive knowledge and beliefs among the transgendered population. Preliminary data from the first twelve patients revealed a young patient population, with ages ranging from 19-25 years. Participants reported a broad range of terms to describe their gender and/or sexuality. Seven of twelve patients surveyed were taking hormone replacement therapy. Five
of twelve patients desired children, with four reporting their fertility to be somewhat important to them. Six had fertility options discussed with them at some point during their treatment, while eight noted that cost was a barrier in banking sperm or eggs. Preliminary results from this young urban population suggests that a moderate number of transgendered patients are aware of their reproductive options and have interest in preserving their fertility.
027-2015. REPRODUCTIVE ENDOCRINOLOGY Effects of Oral Contraceptive Pills on Mood: Lessons Learned from Longitudinal Studies ERIN MILLER*, BENICIO N. FREYy Calgary, AB; Hamilton, ON Oral Contraceptive Pills (OCP) are widely used by women of reproductive age and their use is increasing overtime. Yet, while OCPs have been shown to ameliorate mood symptoms in some women, mood changes are also commonly reported as side effects. The objective of this systematic literature review was to determine the effects of OCP on mood symptoms among healthy women using OCPs for contraception. We included prospective, longitudinal studies with clear comparison groups of either baseline versus post OCP use or case-control studies comparing women with or without OCP treatment. Despite the considerable variability in operational definitions of depression or negative affect, the majority of studies demonstrated no effect of OCP on depressive symptoms when compared with control or baseline data. While studies of manic symptoms were not available, irritability and mood swings related to the premenstrual phase were assessed. Results are equivocal with half the studies showing improvement in symptoms with OCP and half showing no difference. Overall, studies lacked standardized assessment tools and often relied on symptom checklists. Future research would benefit from the development and validation of a convenient tool for the assessment of mood symptoms across the menstrual cycle.
028-2015. GENETICS Effect of Autoimmunity Risk Loci on the Honeymoon Phase in Type 1 Diabetes MANDANA MOOSAVI*, CONSTANTIN POLYCHRONAKO Vancouver, BC; Montréal, QC 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 we selected 177 patients whom we had dense genotyping results of Single-nucleotide Polymorphisms (SNPs) from our previous genome wide association studies. 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 (PTGER 4) to reach statistical significance (P ¼0.0067), in determining a larger proportion of T1DM patients with a detectable honeymoon phase. This polymorphism determines risk for inflammatory bowel disease but not T1DM. Conclusion: By showing the role of PTGER 4 in autoimmune diseases and its effect on glucose response by beta cells, 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
Abstracts / Can J Diabetes 39 (2015) 529e547
insight in to pathogenesis of T1DM and the mechanism of the honeymoon phase.
029-2015.
CLINICAL CARE
Triple Metabolic Therapy in Patients with Advanced Malignancy DAVID MORRIS*y Montréal, QC Recent evidence has supported the positive impact of Metformin (MF) and HMG-CoA reductase inhibitors on patients with malignant disease. Further, in-vitro studies suggest that Histone deacetylase inhibitors (HDACI) including Valproic Acid (VPA) modify malignant cellular differentiation and sensitivity to therapy. Since genomic instability reduces the long-term impact of single therapy, I present here anecdotal reports of diabetic patients with advanced pancreatic malignancy who received conventional treatment with MF, Simvastatin (SV) and additional VPA as a sedative. Method: 8 insulin treated patients, 4 with inoperable disease and 4 with partial removal of tumour are reported here. MF doses were 500mg bid to 850mg bid to assist glycemic control; Simvastatin doses were 20mg to 40mg to control LDL-Cholesterol. VPA dosage varied from 250mg to 500mg nightly to achieve sedation, and VPA levels were routinely followed. Results: Inoperable patients: All had extensive abdominal disease and had received initial chemotherapy for 2-3 months. All survived between 15 and 20 months following diagnosis. No patients suffered any side effects from the medication save drowsiness on VPA at 500mg daily (1 patient). Of the patients who had resection, 3 are alive at between 3 and 4 years following surgery. One had his Metformin therapy stopped because of renal insufficiency and is currently suffering from multiple metastatic disease. One patient succumbed at 18 months. These case reports suggest a role for multiple metabolic therapy in the management of advanced malignancy.
030-2015.
OBESITY
Pregnancies Following Bariatric Surgery in a Couple with Morbid Obesity DAVID MORRIS* Montréal, QC A couple with morbid obesity (Male BMI 47 Female BMI 45.6 KgjM2) presented with infertility despite 4 courses of In Vitro Fertilization (IVF) with Intra-cytoplasmic sperm injection and other interventions. The 44 year old husband had severe oligospermia and asthenozoospermia associated with hypogonadotropic hypogonadism (Total Testosterone repeatedly below 5nmol-l, LH repeatedly below 3 iu-l). He also suffered from Type 2 diabetes, Sleep Apnoea, Hyplerlipdemia and Hypertension. His 38 year old wife had Polycystic Ovary Syndrome with severe oligomenorrhoea. She was also diabetic and hypertensive. Both patients were receiving optimized diabetic therapy including Metformin at 850mg twice daily. Following discussion it was agreed that Bariatric Surgery was the best approach to their Metabolic problems. Six months later both received Roux-en-Y surgery and subsequently successfully lost weight (the husband losing 75kg and his wife 45kg in one year). His wife became spontaneously pregnant 13 months following surgery, at which time the husband’s sperm count was 45 million with 15% motility, and his serum Testosterone had risen to 12.8 nmol-l. A son was born at full term following a well-controlled diabetic pregnancy. Six weeks later the wife became spontaneously pregnant again, and has subsequently delivered another male infant, this time prematurely at 34 weeks. The Reproductive and Metabolic pathologies of both patients remain much improved.
537
This is the first report of a successful reproductive outcome following Bariatric Surgery of both partners.
031-2015. CLINICAL CARE Systematic Review of the Effects of Continuous Glucose Monitoring on Metabolic Control in Children and Adolescents with Type 1 Diabetes KRYSTIE ROBINSON-VINCENT* Toronto, ON Background: Rigorous metabolic control helps delay long term health complications in children with Type 1 diabetes (T1D). Continuous subcutaneous insulin infusion (CSII) with continuous glucose monitoring (CGM) provides valuable information regarding blood glucose levels that is not available with self-monitoring of blood glucose (SMBG) alone. Objective: To critically appraise the research evidence on metabolic control in children diagnosed with T1D using CGM. Methods: Published studies evaluating metabolic control in children with T1D where CGM was used were evaluated. Electronic searches were conducted in MEDLINE, EMBASE, Health and Psychosocial Instruments, and Ovid Healthstar. The articles were reviewed and assessed for methodological quality. Of the 2109 published articles on CGM, only 20 met the inclusion criteria and were included in the analysis. Results: The review yielded nine randomized controlled trials (RCTs) and eleven non-randomized controlled trials. The studies included 2398 children and adolescents with T1D ranging in age from 2-19 years with a diabetes duration ranging from 0.2 to 15 years, with 55% of children using CSII for diabetes management. Significant improvements in HbA1c were found in only eight studies and the remaining 12 studies did not reveal significant improvements in HbA1c between-groups (n¼6) or between the first- and second-time point (n¼6). Conclusions: There are the beginnings of an evidence base indicating that CGM may lead to improved metabolic control compared to SMBG alone in children with T1D. However, future studies using a more rigorous study design (RCT) are required to build on this evidence base.
032-2015. OBESITY Decline in Obesity Prevalence in Canadian Children: An Analysis of the Canadian Community Health and Health Measure Surveys CELIA RODD*, ATUL K. SHARMA Winnipeg, MB Background: Previous studies on the Canadian Community Health Survey (CCHS) demonstrated an increase in the prevalence of overweight or obesity in Canadian children from 23.3% to 34.7% (1978e2004). Background: This study examines newer data from the Canadian Health Measures Survey (CHMS, 2007-2013) and applies new reference charts for weight, waist-circumference, and waist-height ratios in North American children to examine trends in anthropometric measures correlated with cardio-metabolic risk. Methods: Directly measured heights and weights were available for 16,251 children aged 2-19y from 2004-2013 in CCHS/CHMS. Zscores for body mass index (BMI), height, and weight were based on the 2014 WHO Growth Charts for Canada, including their new extension of weight-for-age beyond 10y. For waist circumference and waist-height ratio, we used new charts from the NHANES III reference population, 1988-1994. Results: Using current WHO definitions based on BMI, the prevalence of obesity declined from 15.5% (95% CI ¼ 14.9-16.3%) to 12.7% (11.6-13.8%, p<0.001) from 2004 to 2013, with a similar decline in the proportion overweight or obese from 33.4 % (32.4-34.3%) to
536
025-2015.
GLUCOSE AND METABOLISM
A Case of Marked Insulin Resistance in a Type 1 Diabetic Patient ALLISON MARTIN*, KIRAN WAQAS Prince Albert, SK Insulin resistance which is not a typical feature of Type 1 diabetes may lead to poor glycemic control and increased risk for microvascular and macrovascular complications. These patients may develop anti-insulin antibodies from previous exposure to animal insulin. Other risk factors for developing anti insulin antibodies include asthma, history of allergies and autoimmunity, These antibodies may act as an antagonist or agonist to the insulin receptor resulting in hyperglycemia or hypoglycemia respectively. We studied a 24 year old Caucasian female with type 1 diabetes diagnosed in 2002. She was referred by her family doctor to the endocrine clinic in June 2014. She reported multiple episodes of hyperglycemia and hypoglycemia and being treated with a continuous subcutaneous insulin infusion of Humalog since 2009. She was requiring 126 units of insulin/day. Her HbA1c was 9.7 % (percent). Her past medical history include asthma, multiple allergies, benign brain tumor and autoimmune thyroid disease. She was previously exposed to animal insulin and was on the oral contraceptive pill. Her family history is significant for autoimmune disorders. Her immunochemistry showed positive anti-glutamic acid decarboxylase (GAD) antibodies and anti-insulin antibodies. We substituted insulin aspart (Novorapid) for Humalog in September 2014. She required less insulin and and her glycemic control improved significantly. Her HbA1c went down by 1.8 % over a period of 6 months. In conclusion, insulin resistance should be considered in Type 1 diabetic patients requiring high doses of insulin with persistently poor glycemic control with no obvious cause. In this case, the patient was not responding to insulin therapy despite good compliance with her diabetes management. We believe she developed some resistance to Humalog which is a human insulin possibly due to blocking antibodies. It is important to recognize this possible complication of insulin therapy and treatment should include a trial of another brand of insulin.
026-2015.
REPRODUCTIVE ENDOCRINOLOGY
Attitudes, Knowledge and Beliefs Regarding Fertility Preservation Among People of Transgendered Experience: Preliminary Results ADAM MILLAR*, BRIAN H.K. KIM, DANA LIVNE-SEGEV, RAY FUNG, KEITH JARVI, ADAM C. MILLAR Toronto, ON The transgendered population has traditionally been excluded from population health and sexuality research. Limited research suggests that many transgendered people have not considered fertility preservation. Modern techniques allow for people of transgender experience to have biological children through cryopreservation of sperm or eggs. It is believed that multiple barriers prevent people of transgender experience from engaging in fertility preservation. This ongoing study examines the attitudes, knowledge and beliefs of people of transgendered experience in regards to fertility. Patients at different stages of transition were sampled from multiple endocrine, psychiatric and family practice clinics in Toronto. Semi-structured questionnaires were distributed during routine medical appointments. The target sample size for this study is 200 patients, making this the largest study to date that will specifically evaluate reproductive knowledge and beliefs among the transgendered population. Preliminary data from the first twelve patients revealed a young patient population, with ages ranging from 19-25 years. Participants reported a broad range of terms to describe their gender and/or sexuality. Seven of twelve patients surveyed were taking hormone replacement therapy. Five
of twelve patients desired children, with four reporting their fertility to be somewhat important to them. Six had fertility options discussed with them at some point during their treatment, while eight noted that cost was a barrier in banking sperm or eggs. Preliminary results from this young urban population suggests that a moderate number of transgendered patients are aware of their reproductive options and have interest in preserving their fertility.
027-2015. REPRODUCTIVE ENDOCRINOLOGY Effects of Oral Contraceptive Pills on Mood: Lessons Learned from Longitudinal Studies ERIN MILLER*, BENICIO N. FREYy Calgary, AB; Hamilton, ON Oral Contraceptive Pills (OCP) are widely used by women of reproductive age and their use is increasing overtime. Yet, while OCPs have been shown to ameliorate mood symptoms in some women, mood changes are also commonly reported as side effects. The objective of this systematic literature review was to determine the effects of OCP on mood symptoms among healthy women using OCPs for contraception. We included prospective, longitudinal studies with clear comparison groups of either baseline versus post OCP use or case-control studies comparing women with or without OCP treatment. Despite the considerable variability in operational definitions of depression or negative affect, the majority of studies demonstrated no effect of OCP on depressive symptoms when compared with control or baseline data. While studies of manic symptoms were not available, irritability and mood swings related to the premenstrual phase were assessed. Results are equivocal with half the studies showing improvement in symptoms with OCP and half showing no difference. Overall, studies lacked standardized assessment tools and often relied on symptom checklists. Future research would benefit from the development and validation of a convenient tool for the assessment of mood symptoms across the menstrual cycle.
028-2015. GENETICS Effect of Autoimmunity Risk Loci on the Honeymoon Phase in Type 1 Diabetes MANDANA MOOSAVI*, CONSTANTIN POLYCHRONAKO Vancouver, BC; Montréal, QC 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 we selected 177 patients whom we had dense genotyping results of Single-nucleotide Polymorphisms (SNPs) from our previous genome wide association studies. 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 (PTGER 4) to reach statistical significance (P ¼0.0067), in determining a larger proportion of T1DM patients with a detectable honeymoon phase. This polymorphism determines risk for inflammatory bowel disease but not T1DM. Conclusion: By showing the role of PTGER 4 in autoimmune diseases and its effect on glucose response by beta cells, 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
Abstracts / Can J Diabetes 39 (2015) 529e547
insight in to pathogenesis of T1DM and the mechanism of the honeymoon phase.
029-2015.
CLINICAL CARE
Triple Metabolic Therapy in Patients with Advanced Malignancy DAVID MORRIS*y Montréal, QC Recent evidence has supported the positive impact of Metformin (MF) and HMG-CoA reductase inhibitors on patients with malignant disease. Further, in-vitro studies suggest that Histone deacetylase inhibitors (HDACI) including Valproic Acid (VPA) modify malignant cellular differentiation and sensitivity to therapy. Since genomic instability reduces the long-term impact of single therapy, I present here anecdotal reports of diabetic patients with advanced pancreatic malignancy who received conventional treatment with MF, Simvastatin (SV) and additional VPA as a sedative. Method: 8 insulin treated patients, 4 with inoperable disease and 4 with partial removal of tumour are reported here. MF doses were 500mg bid to 850mg bid to assist glycemic control; Simvastatin doses were 20mg to 40mg to control LDL-Cholesterol. VPA dosage varied from 250mg to 500mg nightly to achieve sedation, and VPA levels were routinely followed. Results: Inoperable patients: All had extensive abdominal disease and had received initial chemotherapy for 2-3 months. All survived between 15 and 20 months following diagnosis. No patients suffered any side effects from the medication save drowsiness on VPA at 500mg daily (1 patient). Of the patients who had resection, 3 are alive at between 3 and 4 years following surgery. One had his Metformin therapy stopped because of renal insufficiency and is currently suffering from multiple metastatic disease. One patient succumbed at 18 months. These case reports suggest a role for multiple metabolic therapy in the management of advanced malignancy.
030-2015.
OBESITY
Pregnancies Following Bariatric Surgery in a Couple with Morbid Obesity DAVID MORRIS* Montréal, QC A couple with morbid obesity (Male BMI 47 Female BMI 45.6 KgjM2) presented with infertility despite 4 courses of In Vitro Fertilization (IVF) with Intra-cytoplasmic sperm injection and other interventions. The 44 year old husband had severe oligospermia and asthenozoospermia associated with hypogonadotropic hypogonadism (Total Testosterone repeatedly below 5nmol-l, LH repeatedly below 3 iu-l). He also suffered from Type 2 diabetes, Sleep Apnoea, Hyplerlipdemia and Hypertension. His 38 year old wife had Polycystic Ovary Syndrome with severe oligomenorrhoea. She was also diabetic and hypertensive. Both patients were receiving optimized diabetic therapy including Metformin at 850mg twice daily. Following discussion it was agreed that Bariatric Surgery was the best approach to their Metabolic problems. Six months later both received Roux-en-Y surgery and subsequently successfully lost weight (the husband losing 75kg and his wife 45kg in one year). His wife became spontaneously pregnant 13 months following surgery, at which time the husband’s sperm count was 45 million with 15% motility, and his serum Testosterone had risen to 12.8 nmol-l. A son was born at full term following a well-controlled diabetic pregnancy. Six weeks later the wife became spontaneously pregnant again, and has subsequently delivered another male infant, this time prematurely at 34 weeks. The Reproductive and Metabolic pathologies of both patients remain much improved.
537
This is the first report of a successful reproductive outcome following Bariatric Surgery of both partners.
031-2015. CLINICAL CARE Systematic Review of the Effects of Continuous Glucose Monitoring on Metabolic Control in Children and Adolescents with Type 1 Diabetes KRYSTIE ROBINSON-VINCENT* Toronto, ON Background: Rigorous metabolic control helps delay long term health complications in children with Type 1 diabetes (T1D). Continuous subcutaneous insulin infusion (CSII) with continuous glucose monitoring (CGM) provides valuable information regarding blood glucose levels that is not available with self-monitoring of blood glucose (SMBG) alone. Objective: To critically appraise the research evidence on metabolic control in children diagnosed with T1D using CGM. Methods: Published studies evaluating metabolic control in children with T1D where CGM was used were evaluated. Electronic searches were conducted in MEDLINE, EMBASE, Health and Psychosocial Instruments, and Ovid Healthstar. The articles were reviewed and assessed for methodological quality. Of the 2109 published articles on CGM, only 20 met the inclusion criteria and were included in the analysis. Results: The review yielded nine randomized controlled trials (RCTs) and eleven non-randomized controlled trials. The studies included 2398 children and adolescents with T1D ranging in age from 2-19 years with a diabetes duration ranging from 0.2 to 15 years, with 55% of children using CSII for diabetes management. Significant improvements in HbA1c were found in only eight studies and the remaining 12 studies did not reveal significant improvements in HbA1c between-groups (n¼6) or between the first- and second-time point (n¼6). Conclusions: There are the beginnings of an evidence base indicating that CGM may lead to improved metabolic control compared to SMBG alone in children with T1D. However, future studies using a more rigorous study design (RCT) are required to build on this evidence base.
032-2015. OBESITY Decline in Obesity Prevalence in Canadian Children: An Analysis of the Canadian Community Health and Health Measure Surveys CELIA RODD*, ATUL K. SHARMA Winnipeg, MB Background: Previous studies on the Canadian Community Health Survey (CCHS) demonstrated an increase in the prevalence of overweight or obesity in Canadian children from 23.3% to 34.7% (1978e2004). Background: This study examines newer data from the Canadian Health Measures Survey (CHMS, 2007-2013) and applies new reference charts for weight, waist-circumference, and waist-height ratios in North American children to examine trends in anthropometric measures correlated with cardio-metabolic risk. Methods: Directly measured heights and weights were available for 16,251 children aged 2-19y from 2004-2013 in CCHS/CHMS. Zscores for body mass index (BMI), height, and weight were based on the 2014 WHO Growth Charts for Canada, including their new extension of weight-for-age beyond 10y. For waist circumference and waist-height ratio, we used new charts from the NHANES III reference population, 1988-1994. Results: Using current WHO definitions based on BMI, the prevalence of obesity declined from 15.5% (95% CI ¼ 14.9-16.3%) to 12.7% (11.6-13.8%, p<0.001) from 2004 to 2013, with a similar decline in the proportion overweight or obese from 33.4 % (32.4-34.3%) to