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OP75 ONCE DAILY INSULIN DEGLUDEC INJECTION SHOWS IMPROVED GLYCEMIC CONTROL IN DIABETES PATIENTS ON INTENSIVE INSULIN THERAPY IN THE REAL-LIFE PRACTICES IN JAPAN
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Oral presentation abstracts / Diabetes Research and Clinical Practice 106S1 (2014) S1–S41
INSULIN-GFP human iPSC reporter line, and are currently examining the mechanisms of action of compound X to induce the pancreatic endocrine differentiation, based on the information of its target molecules and by gene expression analyses on purified INS(+) cells generated with compound X. Conclusion: We have identified one small molecule that facilitates the differentiation of human iPS/ES cells into pancreatic endocrine cells including insulin-producing b-like cells in vitro. Reference(s) [1] Kunisada Y, Tsubooka-Yamazoe N, Shoji M, Hosoya M. Small molecules induce efficient differentiation into insulinproducing cells from human induced pluripotent stem cells. Stem Cell Res 2012; 8: 274–84. [2] Chen S, Borowiak M, Fox JL, Maehr R, Osafune K, Davidow L, Lam K, Peng LF, Schreiber SL, Rubin LL, Melton D. A small molecule that directs differentiation of human ESCs into the pancreatic lineage. Nat Chem Biol. 2009 Apr; 5(4): 258–65.
OP74 EFFICACY AND SAFETY OF THE DPP-4 INHIBITOR COMBINED WITH INSULIN THERAPY IN PATIENTS WITH TYPE 2 DIABETES: A SYSTEMATIC REVIEW AND META-ANALYSIS S.H. Min1 , Y.G. Kim1 , S.Y. Hahn2 , T.J. Oh1 , E.K. Kim1 , K.S. Park1 , Y.M. Cho1 . 1 Internal medicine, 2 Medical Research Collaborating Center, Seoul National University College of Medicine, Seoul, Korea, Republic of Background: The dipeptidyl peptidase-4 (DPP-4) inhibitors are novel anti-diabetic agents used in the treatment of type 2 diabetes. They have shown glucose-lowering effect even in patients who were treated with insulin. In this study, we conducted a systematic review and meta-analysis on the efficacy and safety of the DPP-4 inhibitor combined with insulin therapy in patients with type 2 diabetes. Method: We conducted an electronic search of Medline, Embase, Lilacs, Cochrane Library and Clinicaltrials.gov databases up to June 2014. Search terms included DPP-4 inhibitor, vildagliptin, sitagliptin, linagliptin, alogliptin, saxagliptin, gemigliptin, dutogliptin, gosogliptin and insulin. Randomized controlled trials were selected if they had at least 12 weeks of treatment duration, compared a DPP-4 inhibitor and insulin combination therapy (INS/DPP4i) with insulin alone (INS) in patients with type 2 diabetes mellitus, and described in English. The primary outcome was the change in hemoglobin A1c (HbA1c). The secondary outcomes included body weight change, fasting plasma glucose (FPG), hypoglycemia, and insulin doses. Result: Of 2,578 potentially relevant studies, 9 studies met the inclusion criteria. INS/DPP4i therapy exhibited a greater HbA1c reduction than INS therapy (weighted mean difference [WMD], −0.55%; 95% CI −0.65, −0.44). A greater reduction in FPG was also observed in INS/DPP4i therapy (WMD, −10.13 mg/dl, 95% CI −14.14, −6.11). Despite better glycemic control, INS/DPP4i did not elicit weight gain (WMD, −0.12 kg; 95% CI −0.50, 0.26). In addition, INS/DPP4i therapy exhibited an insulin sparing effect compared to INS therapy (WMD, −4.10 units per day; 95% CI −7.40, −0.79). The incidence of hypoglycemia was similar between INS/DPP4i and INS therapy (relative risk [RR], 0.99; 95% CI 0.77, 1.28). We conducted subgroup analyses according to the insulin titration method, which was either stable dose insulin or titrating insulin doses regimen. Compared to the stable dose insulin regimen, the risk of hypoglycemia tended to be lower in patients with titrating insulin doses regimen. Conclusion: Combined DPP-4 inhibitor and insulin therapy significantly improved glycemic control without increasing the risk of hypoglycemia and weight gain and exhibited an insulin sparing effect in patients with type 2 diabetes. Therefore, adding a DPP-4 inhibitor to a patient with poorly
controlled type 2 diabetes under insulin therapy would be a good treatment option. To confirm whether insulin titration regimens affect the incidence of hypoglycemia with insulin and DPP-4 inhibitor combination therapy, randomized controlled trials are mandatory.
OP75 ONCE DAILY INSULIN DEGLUDEC INJECTION SHOWS IMPROVED GLYCEMIC CONTROL IN DIABETES PATIENTS ON INTENSIVE INSULIN THERAPY IN THE REAL-LIFE PRACTICES IN JAPAN H. Fujii1 , S. Ito2 , K. Kanno3 , M. Kato4 , N. Kato4 , H. Kondo5 , N. Yoshida5 , M. Morita5 , R. Sato6 , H. Takamura7 , M. Takesue8 , E. Kodani9 , H. Daikoku10 , Y. Watanabe1 , Y. Kawagoe1 , M. Nogawa11 , T. Miyakawa11 , M. Kitaoka12 . 1 Tama-center Mirai Clinic, Tama-city, 2 Ito Clinic, Fuchu-city, 3 Kanno Clinic, Mitaka-city, 4 Kato Clinic, Katsushika-ku, 5 Kondo Clinic, Kodaira-city, 6 Kunitachinaika Clinic, Kunitachi-city, 7 Takamura Clinic, Fussa-city, 8 Takesue Clinic, Mitaka-city, 9 Internal Medicine and Cardiology, Nippon Medical School Tama-Nagayama Hospital, Tama-city, 10 Showa General Hospital, Kodaira-city, 11 Kunitachi Mirai Clinic, Kunitachi-city, 12 NPO West Tokyo Diabetes Association, Kokubunji-city, Japan Background: Japanese diabetes patients tend to need relatively less basal insulin rate (around 40%) because of better insulin sensitivity in spite of high carbohydrate consumption. For better control and prevention of hypoglycemia, split basal injection into twice (in the morning and in the evening) is also common. The new long-acting insulin analog insulin degludec has been available in Japan since 2013. It forms “multi-hexamers ” subcutaneously, prolonging its half-life. TRAIN (TResiba Analog Insulin in Nishi-Tokyo) 2 is a multicenter observational study which aimed to switch existing basal insulin to insulin degludec in patients on intensive insulin therapy, approved by IRB of the West Tokyo Diabetes Association. Outcomes included change in HbA1c, body weight, insulin dose and day and nighttime hypoglycemia. Method: We included the patients on intensive insulin therapy (4 times or more injections/day). Basal insulin was switched to the same or lower dose of degludec once a day, and followed for 6 months. Treatment goal was a fasting glucose less than 150 mg/dL. Result: 131 patients from 10 faculties participated. 85 (65%) were type 1 diabetes, 79 (60%) were female. Mean age was 57.9 (SD: 15.8), HbA1c was 7.98 (1.08) %, BMI 23.3 (3.74), previously used glargine (n = 66; 50%), detemir (62) and NPH (3). HbA1c improved slightly but significantly from 7.98% to 7.83% in average, body weight was slightly gain from 59.5 to 60.5 kg. Between type1 and type2 patients: Although their sex and age was not significantly different, BMI (21.9 vs. 26.1), duration of illness (15.6 vs. 23.2 years) and post-prandial insulin secretion (0.48 vs. 1.48 ng/ml) was different. The rate of using glargine previously was higher (57.3 vs. 42.2%), splitting into twice basal insulin injection was more common (70.0 vs. 38.8%). Glycemic control during the study was not significantly different between groups. Comparing by previous basal insulins: Glargine was tended to be split twice less than detemir (46.6 vs, 53.4%; p = 0.18). and used by type 1 more (57.3 vs 42.2%; p = 0.10). At the beginning of this study, the dose of bolus and basal insulin and its ratio was not significantly different among two previous insulin users, however 6 months later, detemir group significantly reduced basal dose; −3.1 (CI: −4.3, −1.9) U/d and total dose/BW; −0.086 (−0.12, −0.054) U/kg/d but not in glargine group. Glycemic control during the study was not significantly different. Between once and twice injecting basal insulin groups: Basal insulin dose and rate had been higher from month 0 (12.9 vs. 20.9 U/d) to month 6 (12.8 vs. 17.8 U/d) in twice daily group, still significantly reduced in 6 months; −3.3 (−4.4, −2.1) U.
Oral presentation abstracts / Diabetes Research and Clinical Practice 106S1 (2014) S1–S41
Glycemic control during the study was not significantly different between groups. No severe hypoglycemia (requiring assistance) was recorded during our study. Frequent nocturnal hypoglycemia (1, 2 times/week or more) decreased especially among type 1 patients; from 19% to 11%. Conclusion: In conclusion, switching to degludec as basal insulin of the patients on intensive insulin therapy slightly improved glycemic control, and decreased nocturnal hypoglycemia. Especially twice injecting group was able to reduce insulin dose without worsening glycemic control by once daily injection of basal insulin. These findings may be related to stability, flatness and longer half-life of degludec.
Insulin resistance OP76 ANALYZING THE METABOLIC PROFILE OF PATIENTS WITH YOUNG-ONSET TYPE 2 DIABETES Z.W. Wee1 , D. Gardner2 , Y.M. Bee2 , S.-Y. Goh2 . 1 National University of Singapore, 2 Endocrinology, Singapore General Hospital, Singapore, Singapore Background: The prevalence of type 2 diabetes mellitus is increasing in young adults in Asia, but little is known about the adequacy of metabolic control or the burden of associated complications in our local population. We aim to describe the disease profile, metabolic control and prevalence of complications in adults with young adult-onset type 2 diabetes mellitus. Method: The Joint Asia Diabetes Evaluation Program electronic portal is a framework for data collection, risk stratification and individualization of treatment. We present baseline data of 319 adults from a tertiary referral outpatient diabetes centre in Singapore (enrolled 2012–2014). Patients were classified as having young-onset diabetes (YOD) if they were diagnosed before the age of 40 years, and as having late-onset diabetes (LOD) if they were diagnosed at 40 years or older. Cross-sectional analyses were performed on participants’ demographic characteristics, metabolic control and presence of vascular complications. Subsequent logistic regressions were performed to further analyze statistically significant relationships found. Result: 30.4% (n = 97) of the cohort had YOD. The mean age of diagnosis was 30.1 for the YOD cohort and 52.1 for the LOD cohort (p < 0.001). There were no differences in gender, ethnic distribution, smoking or alcohol consumption between the young-onset group and the late-onset group. Individuals with YOD were more likely to have first degree family history of diabetes (RR 1.62, 95% CI 1.04–2.54), obesity (RR 1.44, 95% CI 1.03–2.02) and more likely to have a longer duration of diabetes (14.0 years vs 9.0 years, p < 0.001). Three metabolic targets were used to assess the entire cohort: HbA1c < 7%, Blood Pressure (BP) < 130/80 mmHg and Low Density Lipoprotein (LDL) < 2.6 mmol/L. YOD adults were more likely not to achieve any target (29.9% vs 16.7%, p < 0.01), while just 1.0% of them managed to achieve all 3 targets. YOD adults also had poorer glycaemic control (Mean HbA1c 9.0% vs 8.2% p < 0.001), despite a greater proportion being on insulin therapy (58.8% vs 28.3%, p < 0.001). They were also less likely to achieve an optimal glycaemic target of HbA1c < 7% (10.3% vs 28.8%, p < 0.001). After correcting for disease duration, the association found became insignificant. There were no statistical differences in macrovascular complication rates. However, YOD adults were more likely to have micro/macroalbuminuria (50.5% vs 35.5%, p = 0.01); this difference became insignificant upon adjusting for disease duration.
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Conclusion: Despite advances in treatment, gaps in care remain. We are particularly concerned with suboptimal metabolic control and higher prevalence of micro- and macroalbuminuria observed in the young-onset group; these were explained by differences in disease duration in the two groups of participants. Thus, due to the greater cumulative life-time exposure to hyperglycaemia and its adverse consequences, much urgency lies in the prompt diagnosis and aggressive control of metabolic risk factors regardless of age of the patient. Reference(s) [1] Yeung et al. Metabolic profiles and treatment gaps in youngonset type 2 diabetes in Asia (the JADE programme): a crosssectional study of a prospective cohort. Lancet Diabetes Endocrinol. 2014 Jul 28 (Epub ahead of print). [2] Song SH. Young-onset type 2 diabetes: no room for complacency. Lancet Diabetes Endocrinol. 2014 Jul 28 (Epub ahead of print). [3] So WY, Chan JC et al. Comprehensive risk assessment of diabetic patients from seven Asian countries: the Joint Asia Diabetes Evaluation (JADE) program. J Diabetes 2011(3), 109– 118. [4] Chan JC, Jia W et al. Diabetes in Asia: Epidemiology, risk factors and pathophysiology. JAMA 2009: 301; 2129–40. [5] Constatino M, Yue D, Wong J et al. Long term complications and mortality in Young-Onset Diabetes. Diabetes Care 2013 July (epub).
OP77 THE RABGAP TBC1D1 PLAYS A CENTRAL ROLE IN EXERCISE REGULATED GLUCOSE METABOLISM IN SKELETAL MUSCLE J. Stoeckli1 , D.E. James2 . 1 Diabetes and Obesity, Garvan Institute of Medical Research, Darlinghurst, 2 Charles Perkins Centre, Sydney University, Sydney, Australia Background: Insulin and exercise stimulate glucose transport in skeletal muscle via independent signaling pathways both of which converge upon intracellular GLUT4 containing vesicles resulting in their translocation to the plasma membrane. The insulin signaling pathway involves the canonical PI3K/Akt pathway and the RabGAP AS160/TBC1D4 has been identified as a major Akt substrate involved in GLUT4 translocation. Exercise-stimulated GLUT4 translocation, on the other hand, involves phosphorylation of the TBC1D4 homolog TBC1D1, by AMPK. To further explore the role of TBC1D1 in GLUT4 translocation and metabolic regulation we created TBC1D1 knock out mice using ES cells from the International Gene Trap Consortium. Method: TBC1D1−/− mice and wildtype littermates underwent extensive metabolic phenotyping, including analysis of body weight, glucose and insulin tolerance tests and in vitro glucose uptake. Tissues lysates were immuoblotted for several total proteins. TBC1D1 cDNA and empty vector were in vivo electroporated into tibialis anterior muscle from TBC1D1−/− and wildtype mice. Exercise endurance and capacity was tested using running protocols on a mouse treadmill and glucose uptake was determined using tracer in cannulated mice. Result: TBC1D1 was expressed at highest levels in muscle and the TBC1D1 protein levels were absent in muscle from TBC1D1−/− mice. GLUT4 levels were reduced by ~40% in white muscle, such as tibialis anterior (TA) or extensor digitorum longus (EDL) from TBC1D1−/− mice. This reduction was rescued by re-expressing TBC1D1 in TA muscle using in vivo electroporation. Even though the TBC1D1−/− mice had reduced GLUT4 levels in some muscles, they had normal insulin-mediated glucose metabolism and body weight. However, TBC1D1−/− showed impaired exercise endurance and furthermore, glucose uptake into EDL in vitro and into white quadriceps in vivo was impaired in response to an AMPK agonist or exercise, respectively.
Oral presentation abstracts / Diabetes Research and Clinical Practice 106S1 (2014) S1–S41
INSULIN-GFP human iPSC reporter line, and are currently examining the mechanisms of action of compound X to induce the pancreatic endocrine differentiation, based on the information of its target molecules and by gene expression analyses on purified INS(+) cells generated with compound X. Conclusion: We have identified one small molecule that facilitates the differentiation of human iPS/ES cells into pancreatic endocrine cells including insulin-producing b-like cells in vitro. Reference(s) [1] Kunisada Y, Tsubooka-Yamazoe N, Shoji M, Hosoya M. Small molecules induce efficient differentiation into insulinproducing cells from human induced pluripotent stem cells. Stem Cell Res 2012; 8: 274–84. [2] Chen S, Borowiak M, Fox JL, Maehr R, Osafune K, Davidow L, Lam K, Peng LF, Schreiber SL, Rubin LL, Melton D. A small molecule that directs differentiation of human ESCs into the pancreatic lineage. Nat Chem Biol. 2009 Apr; 5(4): 258–65.
OP74 EFFICACY AND SAFETY OF THE DPP-4 INHIBITOR COMBINED WITH INSULIN THERAPY IN PATIENTS WITH TYPE 2 DIABETES: A SYSTEMATIC REVIEW AND META-ANALYSIS S.H. Min1 , Y.G. Kim1 , S.Y. Hahn2 , T.J. Oh1 , E.K. Kim1 , K.S. Park1 , Y.M. Cho1 . 1 Internal medicine, 2 Medical Research Collaborating Center, Seoul National University College of Medicine, Seoul, Korea, Republic of Background: The dipeptidyl peptidase-4 (DPP-4) inhibitors are novel anti-diabetic agents used in the treatment of type 2 diabetes. They have shown glucose-lowering effect even in patients who were treated with insulin. In this study, we conducted a systematic review and meta-analysis on the efficacy and safety of the DPP-4 inhibitor combined with insulin therapy in patients with type 2 diabetes. Method: We conducted an electronic search of Medline, Embase, Lilacs, Cochrane Library and Clinicaltrials.gov databases up to June 2014. Search terms included DPP-4 inhibitor, vildagliptin, sitagliptin, linagliptin, alogliptin, saxagliptin, gemigliptin, dutogliptin, gosogliptin and insulin. Randomized controlled trials were selected if they had at least 12 weeks of treatment duration, compared a DPP-4 inhibitor and insulin combination therapy (INS/DPP4i) with insulin alone (INS) in patients with type 2 diabetes mellitus, and described in English. The primary outcome was the change in hemoglobin A1c (HbA1c). The secondary outcomes included body weight change, fasting plasma glucose (FPG), hypoglycemia, and insulin doses. Result: Of 2,578 potentially relevant studies, 9 studies met the inclusion criteria. INS/DPP4i therapy exhibited a greater HbA1c reduction than INS therapy (weighted mean difference [WMD], −0.55%; 95% CI −0.65, −0.44). A greater reduction in FPG was also observed in INS/DPP4i therapy (WMD, −10.13 mg/dl, 95% CI −14.14, −6.11). Despite better glycemic control, INS/DPP4i did not elicit weight gain (WMD, −0.12 kg; 95% CI −0.50, 0.26). In addition, INS/DPP4i therapy exhibited an insulin sparing effect compared to INS therapy (WMD, −4.10 units per day; 95% CI −7.40, −0.79). The incidence of hypoglycemia was similar between INS/DPP4i and INS therapy (relative risk [RR], 0.99; 95% CI 0.77, 1.28). We conducted subgroup analyses according to the insulin titration method, which was either stable dose insulin or titrating insulin doses regimen. Compared to the stable dose insulin regimen, the risk of hypoglycemia tended to be lower in patients with titrating insulin doses regimen. Conclusion: Combined DPP-4 inhibitor and insulin therapy significantly improved glycemic control without increasing the risk of hypoglycemia and weight gain and exhibited an insulin sparing effect in patients with type 2 diabetes. Therefore, adding a DPP-4 inhibitor to a patient with poorly
controlled type 2 diabetes under insulin therapy would be a good treatment option. To confirm whether insulin titration regimens affect the incidence of hypoglycemia with insulin and DPP-4 inhibitor combination therapy, randomized controlled trials are mandatory.
OP75 ONCE DAILY INSULIN DEGLUDEC INJECTION SHOWS IMPROVED GLYCEMIC CONTROL IN DIABETES PATIENTS ON INTENSIVE INSULIN THERAPY IN THE REAL-LIFE PRACTICES IN JAPAN H. Fujii1 , S. Ito2 , K. Kanno3 , M. Kato4 , N. Kato4 , H. Kondo5 , N. Yoshida5 , M. Morita5 , R. Sato6 , H. Takamura7 , M. Takesue8 , E. Kodani9 , H. Daikoku10 , Y. Watanabe1 , Y. Kawagoe1 , M. Nogawa11 , T. Miyakawa11 , M. Kitaoka12 . 1 Tama-center Mirai Clinic, Tama-city, 2 Ito Clinic, Fuchu-city, 3 Kanno Clinic, Mitaka-city, 4 Kato Clinic, Katsushika-ku, 5 Kondo Clinic, Kodaira-city, 6 Kunitachinaika Clinic, Kunitachi-city, 7 Takamura Clinic, Fussa-city, 8 Takesue Clinic, Mitaka-city, 9 Internal Medicine and Cardiology, Nippon Medical School Tama-Nagayama Hospital, Tama-city, 10 Showa General Hospital, Kodaira-city, 11 Kunitachi Mirai Clinic, Kunitachi-city, 12 NPO West Tokyo Diabetes Association, Kokubunji-city, Japan Background: Japanese diabetes patients tend to need relatively less basal insulin rate (around 40%) because of better insulin sensitivity in spite of high carbohydrate consumption. For better control and prevention of hypoglycemia, split basal injection into twice (in the morning and in the evening) is also common. The new long-acting insulin analog insulin degludec has been available in Japan since 2013. It forms “multi-hexamers ” subcutaneously, prolonging its half-life. TRAIN (TResiba Analog Insulin in Nishi-Tokyo) 2 is a multicenter observational study which aimed to switch existing basal insulin to insulin degludec in patients on intensive insulin therapy, approved by IRB of the West Tokyo Diabetes Association. Outcomes included change in HbA1c, body weight, insulin dose and day and nighttime hypoglycemia. Method: We included the patients on intensive insulin therapy (4 times or more injections/day). Basal insulin was switched to the same or lower dose of degludec once a day, and followed for 6 months. Treatment goal was a fasting glucose less than 150 mg/dL. Result: 131 patients from 10 faculties participated. 85 (65%) were type 1 diabetes, 79 (60%) were female. Mean age was 57.9 (SD: 15.8), HbA1c was 7.98 (1.08) %, BMI 23.3 (3.74), previously used glargine (n = 66; 50%), detemir (62) and NPH (3). HbA1c improved slightly but significantly from 7.98% to 7.83% in average, body weight was slightly gain from 59.5 to 60.5 kg. Between type1 and type2 patients: Although their sex and age was not significantly different, BMI (21.9 vs. 26.1), duration of illness (15.6 vs. 23.2 years) and post-prandial insulin secretion (0.48 vs. 1.48 ng/ml) was different. The rate of using glargine previously was higher (57.3 vs. 42.2%), splitting into twice basal insulin injection was more common (70.0 vs. 38.8%). Glycemic control during the study was not significantly different between groups. Comparing by previous basal insulins: Glargine was tended to be split twice less than detemir (46.6 vs, 53.4%; p = 0.18). and used by type 1 more (57.3 vs 42.2%; p = 0.10). At the beginning of this study, the dose of bolus and basal insulin and its ratio was not significantly different among two previous insulin users, however 6 months later, detemir group significantly reduced basal dose; −3.1 (CI: −4.3, −1.9) U/d and total dose/BW; −0.086 (−0.12, −0.054) U/kg/d but not in glargine group. Glycemic control during the study was not significantly different. Between once and twice injecting basal insulin groups: Basal insulin dose and rate had been higher from month 0 (12.9 vs. 20.9 U/d) to month 6 (12.8 vs. 17.8 U/d) in twice daily group, still significantly reduced in 6 months; −3.3 (−4.4, −2.1) U.
Oral presentation abstracts / Diabetes Research and Clinical Practice 106S1 (2014) S1–S41
Glycemic control during the study was not significantly different between groups. No severe hypoglycemia (requiring assistance) was recorded during our study. Frequent nocturnal hypoglycemia (1, 2 times/week or more) decreased especially among type 1 patients; from 19% to 11%. Conclusion: In conclusion, switching to degludec as basal insulin of the patients on intensive insulin therapy slightly improved glycemic control, and decreased nocturnal hypoglycemia. Especially twice injecting group was able to reduce insulin dose without worsening glycemic control by once daily injection of basal insulin. These findings may be related to stability, flatness and longer half-life of degludec.
Insulin resistance OP76 ANALYZING THE METABOLIC PROFILE OF PATIENTS WITH YOUNG-ONSET TYPE 2 DIABETES Z.W. Wee1 , D. Gardner2 , Y.M. Bee2 , S.-Y. Goh2 . 1 National University of Singapore, 2 Endocrinology, Singapore General Hospital, Singapore, Singapore Background: The prevalence of type 2 diabetes mellitus is increasing in young adults in Asia, but little is known about the adequacy of metabolic control or the burden of associated complications in our local population. We aim to describe the disease profile, metabolic control and prevalence of complications in adults with young adult-onset type 2 diabetes mellitus. Method: The Joint Asia Diabetes Evaluation Program electronic portal is a framework for data collection, risk stratification and individualization of treatment. We present baseline data of 319 adults from a tertiary referral outpatient diabetes centre in Singapore (enrolled 2012–2014). Patients were classified as having young-onset diabetes (YOD) if they were diagnosed before the age of 40 years, and as having late-onset diabetes (LOD) if they were diagnosed at 40 years or older. Cross-sectional analyses were performed on participants’ demographic characteristics, metabolic control and presence of vascular complications. Subsequent logistic regressions were performed to further analyze statistically significant relationships found. Result: 30.4% (n = 97) of the cohort had YOD. The mean age of diagnosis was 30.1 for the YOD cohort and 52.1 for the LOD cohort (p < 0.001). There were no differences in gender, ethnic distribution, smoking or alcohol consumption between the young-onset group and the late-onset group. Individuals with YOD were more likely to have first degree family history of diabetes (RR 1.62, 95% CI 1.04–2.54), obesity (RR 1.44, 95% CI 1.03–2.02) and more likely to have a longer duration of diabetes (14.0 years vs 9.0 years, p < 0.001). Three metabolic targets were used to assess the entire cohort: HbA1c < 7%, Blood Pressure (BP) < 130/80 mmHg and Low Density Lipoprotein (LDL) < 2.6 mmol/L. YOD adults were more likely not to achieve any target (29.9% vs 16.7%, p < 0.01), while just 1.0% of them managed to achieve all 3 targets. YOD adults also had poorer glycaemic control (Mean HbA1c 9.0% vs 8.2% p < 0.001), despite a greater proportion being on insulin therapy (58.8% vs 28.3%, p < 0.001). They were also less likely to achieve an optimal glycaemic target of HbA1c < 7% (10.3% vs 28.8%, p < 0.001). After correcting for disease duration, the association found became insignificant. There were no statistical differences in macrovascular complication rates. However, YOD adults were more likely to have micro/macroalbuminuria (50.5% vs 35.5%, p = 0.01); this difference became insignificant upon adjusting for disease duration.
S39
Conclusion: Despite advances in treatment, gaps in care remain. We are particularly concerned with suboptimal metabolic control and higher prevalence of micro- and macroalbuminuria observed in the young-onset group; these were explained by differences in disease duration in the two groups of participants. Thus, due to the greater cumulative life-time exposure to hyperglycaemia and its adverse consequences, much urgency lies in the prompt diagnosis and aggressive control of metabolic risk factors regardless of age of the patient. Reference(s) [1] Yeung et al. Metabolic profiles and treatment gaps in youngonset type 2 diabetes in Asia (the JADE programme): a crosssectional study of a prospective cohort. Lancet Diabetes Endocrinol. 2014 Jul 28 (Epub ahead of print). [2] Song SH. Young-onset type 2 diabetes: no room for complacency. Lancet Diabetes Endocrinol. 2014 Jul 28 (Epub ahead of print). [3] So WY, Chan JC et al. Comprehensive risk assessment of diabetic patients from seven Asian countries: the Joint Asia Diabetes Evaluation (JADE) program. J Diabetes 2011(3), 109– 118. [4] Chan JC, Jia W et al. Diabetes in Asia: Epidemiology, risk factors and pathophysiology. JAMA 2009: 301; 2129–40. [5] Constatino M, Yue D, Wong J et al. Long term complications and mortality in Young-Onset Diabetes. Diabetes Care 2013 July (epub).
OP77 THE RABGAP TBC1D1 PLAYS A CENTRAL ROLE IN EXERCISE REGULATED GLUCOSE METABOLISM IN SKELETAL MUSCLE J. Stoeckli1 , D.E. James2 . 1 Diabetes and Obesity, Garvan Institute of Medical Research, Darlinghurst, 2 Charles Perkins Centre, Sydney University, Sydney, Australia Background: Insulin and exercise stimulate glucose transport in skeletal muscle via independent signaling pathways both of which converge upon intracellular GLUT4 containing vesicles resulting in their translocation to the plasma membrane. The insulin signaling pathway involves the canonical PI3K/Akt pathway and the RabGAP AS160/TBC1D4 has been identified as a major Akt substrate involved in GLUT4 translocation. Exercise-stimulated GLUT4 translocation, on the other hand, involves phosphorylation of the TBC1D4 homolog TBC1D1, by AMPK. To further explore the role of TBC1D1 in GLUT4 translocation and metabolic regulation we created TBC1D1 knock out mice using ES cells from the International Gene Trap Consortium. Method: TBC1D1−/− mice and wildtype littermates underwent extensive metabolic phenotyping, including analysis of body weight, glucose and insulin tolerance tests and in vitro glucose uptake. Tissues lysates were immuoblotted for several total proteins. TBC1D1 cDNA and empty vector were in vivo electroporated into tibialis anterior muscle from TBC1D1−/− and wildtype mice. Exercise endurance and capacity was tested using running protocols on a mouse treadmill and glucose uptake was determined using tracer in cannulated mice. Result: TBC1D1 was expressed at highest levels in muscle and the TBC1D1 protein levels were absent in muscle from TBC1D1−/− mice. GLUT4 levels were reduced by ~40% in white muscle, such as tibialis anterior (TA) or extensor digitorum longus (EDL) from TBC1D1−/− mice. This reduction was rescued by re-expressing TBC1D1 in TA muscle using in vivo electroporation. Even though the TBC1D1−/− mice had reduced GLUT4 levels in some muscles, they had normal insulin-mediated glucose metabolism and body weight. However, TBC1D1−/− showed impaired exercise endurance and furthermore, glucose uptake into EDL in vitro and into white quadriceps in vivo was impaired in response to an AMPK agonist or exercise, respectively.