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Late Breaking Abstracts July 2013 | Volume 62 | Suppl Late Breaking Abstracts July 2013 | Volume 62 | Suppl. 1A | www.diabetes.org/diabetes Late Breaking Abstracts LB1 Subject Index LB56 Abstract Author Index LB59 Abstract Author Disclosure Information LB66 scientificsessions.diabetes.org ACUTE AND CHRONIC COMPLICATIONS COMPLICATIONS—HYPOGLYCEMIA 1-LB Peripheral GABA Infusion in Diabetic Rats Enhances the Glucagon Counterregulation and Protects Against Insulin Hypoglycemia LEON S. FARHY, PATTIE H. HELLMANN, ANTHONY L. MCCALL, Charlottesville, VA Glucagon counterregulation (GCR) is often defective in type 1 diabetes (T1DM). Our animal, clinical, and modeling studies suggest that hyperglucagonemia contributes to the GCR impairment and alpha-cell inhibitors (ACI) may be used to improve GCR. This study further supports this hypothesis by showing that constant peripheral GABA infusion enhances GCR and protects against hypoglycemia. Blood glucose (BG) and glucagon hypoglycemia responses were tested in 2 groups of conscious STZ-treated male Wistar rats. BG was lowered to ~150mg/dL after which a constant (50uL/min) jugular iv infusion of saline (N=7) or 4mg/mL of GABA (N=9) started (t=-10 min). At t=0 min, a 12U/kg iv insulin bolus was given. Blood sampling was done every 10min for BG and glucagon from t= -10 to 80 min. GCR was estimated via the product R={mean of 2 lowest BG values from t=10 to 40 min} x {mean glucagon from t= 50 to 80 min}. R measures the BG level-specific GCR with higher values indicating a better response. This design was chosen over a glucose clamp to avoid over- insulinization at the time of GCR. Even though the initial (t< 20 min) glucagon Supported by: Boehringer Ingelheim Pharmaceuticals, Inc. fold change relative to the basal was lower with GABA vs. saline (mean±SD) (0.9±0.28 vs. 1.4±0.54, p=0.04), the later (after t=50 min) BG level-specific GCR was 72% higher in the GABA group: 3159±900.5 vs. 2273±690.4, p=0.04. The 3-LB GABA treated group was also better protected against hypoglycemia assessed The Effects of Diabetes Duration on Hypoglycemia Symptom Intensity by the two lowest BG values after the insulin bolus: 68±6.5 md/dL vs. 57±9.5 and Prevalence of Impaired Awareness of Hypoglycemia mg/dL; p=0.02. These results are predicted by our mathematical GCR model in SANDRA E. OLSEN, BJØRN OLAV ÅSVOLD, BRIAN M. FRIER, SILJE A. EGGEN, which reduction of basal glucagon by ACI enhances the defective GCR. They LIZ-IREN HANSEN, MARIT R. BJØRGAAS, Trondheim, Norway, Edinburgh, United differ from prior animal work where ACI were given intrapancreatically and Kingdom switched off at hypoglycemia. Thus, for the first time GCR enhancement is Diabetes duration influences hypoglycemia symptom profile and prevalence achieved by peripheral ACI infusion without a switch-off or other manipulation. of impaired awareness of hypoglycemia (IAH); viz. a diminished ability to Such treatment could lead to novel strategies for glycemia control in T1DM perceive onset of hypoglycemia. By questionnaire, hypoglycemia symptoms with enhanced protection against hypoglycemia. and prevalence of IAH were assessed in an outpatient population with type 1 Supported by: NIH (RO1DK082805) diabetes. Symptom presence and intensity were measured by the Edinburgh Hypoglycaemia Scale, using a Likert scale of 1 to 7. Hypoglycemia awareness was assessed by the method of Gold et al., based on the question “do you 2-LB know when your hypos are commencing?”, using a scale from 1 to 7 (1 = Lower Risk of Hypoglycemia in Elderly Type 2 Diabetes Patients when always aware, 7 = never aware; ≥ 4 = IAH, < 4 = normal awareness (NAH)). Linagliptin is Added to Basal Insulin: An Exploratory Analysis The response rate was 70% (445/636). IAH was present in 17% (CI: 14-21%). SILVIO E. INZUCCHI, MICHAEL NAUCK, MAXIMILIAN VON EYNATTEN, UWE With progressive diabetes duration, the prevalence of IAH increased (from HEHNKE, HANS-JUERGEN WOERLE, ROBERT R. HENRY, New Haven, CT, Bad 3 % for duration 2-9 years to 28 % for duration ≥ 30 years, p for trend < Lauterberg im Harz, Germany, Ingelheim, Germany, San Diego, CA 0.001), the mean intensity of autonomic (A) symptoms declined (p for trend < Elderly T2DM patients (pts) with long-standing disease often require insulin 0.001) (Fig.1), the intensity of trembling and hunger decreased (p < 0.001 and (INS) therapy, yet hypoglycemia is a major concern. It has recently been shown p = 0.004, respectively), while the mean intensity of neuroglycopenic (NG) that linagliptin (LINA) added to stable basal INS in elderly T2DM pts reduced symptoms did not change (p = 0.55). The mean (SD) ratio of NG/A symptoms HbA1c by -0.77% vs. placebo (PBO), notably with less hypoglycemia. Here we was higher in IAH than in NAH subjects (1.16 (0.43) vs. 1.01 (0.33), p = 0.001). further explore hypoglycemia risk in these pts (n=247; mean±SD age 74±4 In conclusion, with progressive diabetes duration, the prevalence of IAH rises yrs, HbA1c 8.2±0.8%) on basal INS (baseline [BL] dose 36±25 U/day) from and the intensity of autonomic symptoms, particularly trembling, declines. two phase 3 studies of 24 and ≥52 weeks. Odds ratios (OR) for overall and Neuroglycopenic symptoms predominated in those with IAH. confirmed hypoglycemia (blood glucose ≤70 mg/dl) were assessed (INS doses did not change notably). Overall (-37%) and confirmed (-34%) hypoglycemia risk was lower with LINA vs. PBO (OR 0.63 [95% CI 0.37-1.10] [Fig] and 0.66 [0.36- 1.21], respectively). Significantly less (-59%) confirmed hypoglycemia was found in LINA pts with mild-moderate BL hyperglycemia (HbA1c 7.5-<9.0%; OR 0.41 [0.21-0.84]; p=0.014). Similar directional trend in hypoglycemia risk with LINA vs. PBO was also observed in pts with BL HbA1c <7.5% (overall OR 0.77) and subgroups for glargine, detemir or NPH (overall OR 0.74, 0.59, 0.49, respectively). Despite significantly reduced HbA1c and no relevant on-trial INS dose reductions, adding LINA to basal INS appears to decrease hypoglycemia risk. This trend is in stark contrast to other oral agents when combined with INS. The biological underpinnings of this phenomenon are unclear but deserving further study. Supported by: Norwegian Diabetes Association ADA-Funded Research For author disclosure information, see page LB66. LB1 ACUTE AND CHRONIC COMPLICATIONS COMPLICATIONS—MaCROVASCUlaR— 6-LB ATHEROSCLEROTIC CaRDIOVASCUlaR DISEASE High Sensitivity Cardiac Troponin I as a Diagnostic Tool for the AND HUMAN DIabETES Presence of Coronary Artery Disease in Stable Diabetic Patients ALEXANDRE SEGRE, ANTONIO CASELLA-FILHO, MARILIA SPRANDEL, CELIA STRUNZ, ALESSANDRA ROGGERIO, ANA CARVALHO, DESIDERIO FAVARATO, 4-LB PAULO REZENDE, RAUL CAVALCANTE. MARANHAO, ROBERTO KALIL, JOSE Limiting Amylin Aggregation Protects the Heart in Diabetes RAMIRES, WHADY HUEB, São Paulo, Brazil FLORIN DESPA, SANDA DESPA, KALEENA JACKSON, BACH LE, TODD HARRIS, Introduction: The emergence of several high sensitivity troponin (hsTroponin) HUA DONG, NING LI, NIPAVAN CHIAMVIMONVAT, KENNETH B. MARGULIES, assays has shown that cardiac troponins can be chronically elevated in HEINRICH TAEGTMEYER, BRUCE HAMMOCK, Davis, CA, Philadelphia, PA, response to cardiovascular comorbidities. In the absence of unstable coronary Houston, TX artery disease, pathophysiological mechanisms as increased demand ischemia Recent data revealed that the islet amyloid polypeptide (IAPP; amylin), an or disturbances of cell membrane integrity are possible causes for troponin amyloidogenic protein making up the pancreatic amyloid in type-2 diabetes leakage. We hypothesized that with a high sensitivity assay, troponin levels mellitus (T2DM), also accumulates in failing hearts from obese or T2DM would be higher in diabetic patients with coronary artery disease (CAD), in patients. Cardiac deposition of amylin accelerates diabetic heart failure in comparison to diabetic patients without coronary artery disease. a T2DM rat model transgenic for human amylin (the HIP rat). In this study, Objective: To evaluate hsTroponin levels in ambulatory diabetic patients we assessed the attachment/incorporation of oligomerized amylin to cardiac with multivessel CAD and diabetic patients with angiographically normal cells in humans and tested the ability of pro-fibrinolytic eicosanoic acids to coronary arteries. reduce amylin deposition and its deleterious cardiac effects in HIP rats. Methods: hsTroponin levels were determinated in 85 diabetic patients: 51 Oligomerized amylin was identified within coronary arteries, cardiac myocytes women (22 with CAD and 29 with normal coronary arteries) and 44 men (34 and atherosclerotic lesions in failing hearts from diabetic humans, but not in with CAD and 10 with normal coronary arteries). Patients were paired by age control hearts. Intriguingly, significant amylin deposition was found in cardiac and body mass index. Both groups of patients had preserved left ventricular cells from patients that developed T2DM post-transplantation, suggesting function measured by ventriculography or echocardiography. that amylin builds up in the heart and may affect myocardial structure and Results: hsTroponin levels were significantly higher (p=0.0005) in diabetic function even in pre-diabetes. To elevate the blood level of eicosanoids and women with CAD (average = 12.95+5.55 pg/mL) in comparison to diabetic block cardiac amylin deposition in HIP rats, we treated animals in pre-diabetic women with normal coronary arteries (average = 8.02+2.62 pg/mL). hs state with an inhibitor of soluble epoxide hydrolase, the enzyme that degrades Troponin levels were also significantly higher (p=0.0086) in diabetic men with endogenous eicosanoids. Treatment doubled the blood concentration of pro- CAD (average=10.60+4.39 pg/mL) in comparison to diabetic men with normal fibrinolytic eicosanoids, which drastically limited the attachment/incorporation coronary arteries (average=6.94+1.67). At a troponin cutoff of 11 pg/mL 90% of oligomerized amylin to cardiac myocytes. Animals in the treated group of diabetic men and 75% of diabetic women had CAD.
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