2011 ada presidents 379-477 - diabetes tomoaki inoue, kunihisa kobayashi, masakazu fujii, eiichi...

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  • A105

    For author disclosure information, see page 785.ADA-Funded Research

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    COMPLICATIONS—HYPOGLYCEMIA

    379-PP Corticotrophin Releasing Hormone Receptor Type 2 in Both Ventro- medial Hypothalamus and Medical Amygdalar Nucleus Suppress Counterregulatory Responses to Acute Hypoglycemia in the Rat XIAONING FAN, STACEY BROWN, YUYAN DING, ROBERT S. SHERWIN, RORY J. MCCRIMMON, New Haven, CT, Dundee, United Kingdom

    Hypoglycemia detection takes place within specialized neurons located within discrete brain regions, e.g. the ventromedial hypothalamus (VMH). We have recently demonstrated the presence of a novel glucose sensing region in the medial amygdalar nucleus (MeA) of the rat. In addition, we also demonstrated that both VMH and MeA glucose-sensing regions were innervated by urocortin 3 (UCN3) containing neurons. UCN3 is an endogenous neuropeptide that acts through binding to the corticotrophin releasing hormone type 2 receptor(CRH-R2), and plays a major role in regulating responses to a variety of physiological and behavioral stresses. To determine whether hypoglycemia- sensing in both VMH and MeA is modulated by CRH-R2-mediated effects we used RNA interference to selectively suppress CRHR2 expression in both brain regions. Ten days prior to study male Sprague-dawley rats were microinjected under general anethesia to either the VMH or MeA with an adeno-associated viral vector (AAV) containing an RNAi targeting CRH-R2 or a control RNAi as well as having chronic vascular catheters inserted. Subsequently, all rats underwent a 90 minute hyperinsulinemic (20 mU/kg/min) hypoglycemic (∼60 mg/dl) clamp study with arterial sampling for counterregulatory hormone responses. During equivalent hypoglycemia, knockdown of CRH-R2 in either the VMH or MeA was found to markedly amplify epinephrine (100% and 88%, respectively) and glucagon (35% and 61%, respectively) responses to hypoglycemia (see Table below; MeA and VMH control studies are combined because CRR responses did not differ between the two; =p

  • A106

    For author disclosure information, see page 785. ADA-Funded Research

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    testing devices for non-invasive detection/quantifi cation of OS, with considerable relevance for the prevention, monitoring and assessment of treat ment effi cacy of diabetic cardiovascular complications.

    Supported by: NIH 1UL1RR031985; K24 DK085223. ADA-Funded Research

    383-PP The Relationship between Coronary Atherosclerotic Burden and Calci - fi ed Coronary Score in Patients with and without Diabetes Mellitus HONGXIA ZHANG, JIE YUAN, JIE LIU, XIAOXIAN TANG, WEIPING JIA, Taiyuan, China, Shanghai, China

    The purpose of the study is to compare the presence of obstructive and non-obstructive coronary artery disease (CAD) as well as calcifi ed coronary artery plaque burden in patients with and without diabetes mellitus (DM). The study population is consisted of 743 individuals (156 diabetics and 587 non- diabetics) suspected CAD but no history of CAD(prior myocardial infarction or myocardial revascularization procedure). All subjects underwent 64-slice CT coronary angiography (CTCA) as part of a health screening evaluation. The per-patient number of diseased coronary segments were determined and each diseased segment was classifi ed as obstructive lesion (luminal narrowing >50%) or not. Coronary calcium score (CCS) was considered too. Detailed information regarding symptoms, physical examination, medical history and risk factors were collected at the time of presentation. CTCA was performed without complications in all 743 patients: 63% male, 59±17 years. Diabetic patients were older (62±13 years vs. 58±10 years, p=0.002), had a higher BMI (26.7 vs. 25.2, p400(p=0.02), obstructive CAD (26.6% vs. 17.2% of patients; p=0.004), and fewer normal coronary arteries (31.3% vs. 47.6%; p

  • A107

    For author disclosure information, see page 785.ADA-Funded Research

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    protein 2 (lamp2)-knockout mice, in which lysosomes do not bind or degrade autophagosomes. Tubulointerstitial lesions induced by protein-overload were exacerbated in both types of mice. These results indicate that obesity and aging suppress proteinuria-induced autophagy in the proximal tubular cells. Decreased autophagy exacerbated tubulointerstitial lesions mediated by proteinuria, suggesting that defi cient autophagy is associated with progressive tubulointerstitial lesions and a poor renal prognosis for diabetic nephropathy.

    386-PP Baseline Hyperfi ltration (HF) Is Associated with Accelerated Rate of Decline in Glomerular Filtration Rate (GFR) in Type 1 but Not in Type 2 Diabetes Mellitus RICHARD J. MACISAAC, SHILPA VERMA, EROSHA PREMARATNE, CLEMENT LO, GEORGE JERMUS, Heidelberg West, Australia

    The aim of this study was to characterise the consequences of HF in type 1 (T1DM) and type 2 diabetes mellitus (T2DM). We examined the relationship between baseline GFR and subsequent decline in GFR over approximately 12.5 years for patients attending a diabetes clinic of a university teaching hospital. Yearly cystatin C measurements were performed and a cystatin C derived GFR (cysGFR) was calculated using the formula: cysGFR = (87/Cystatin C)-4.2. Baseline age unadjusted GFR thresholds (ml/min/1.73m2) were used, i.e., >130 for HF, 90-130 for normofi ltration and 40 years. The main outcome was to determine if baseline HF was associated with an accelerated rate of decline of GFR. Mean gradients of decline in GFR were obtained by linear regression. The baseline charateristics of the patients studied are shown in Table 1.

    Parameter T1DM (N=98) T2DM (N=143) Age at baseline (years) 37.1 57.7 Duration of diabetes (years) 12.2 8.4 Duration of diabetes (years) 12.8 12.9 Male:Female ratio 58:40 70:73

    Baseline HF was seen in 17 % of T1DM and 11 % of T2DM patients.

    Age adjusted GFR category

    T1 DM baseline GFR

    (ml/min/1.73m2)

    Type 1 DM rate of GFR

    decline (ml/min/

    1.73m2/year)

    Type 2 DM basline GFR

    (ml/min/1.73m2)

    Type 2 DM rate of GFR

    decline (ml/min/

    1.73m2/year)

    Hyperfi ltration 140.9+ 3.5 (n=17) -4.26* 129.5+3.8 (n=16) -2.03 Normofi ltration 105.8+1.3 (n=71) -0.95 91.1+1.3 (n=110) -1.63 Hypofi ltration 64.1+ 6.2 (n=10) -1.64 62.9+3.0 (n=17) -2.12

    * p < 0.001 vs normofi ltration.

    Results were similar using age unadjusted threshold for HF. For all HF patients, approximately half showed a true GFR decline with a fi nal GFR

  • A108

    For author disclosure information, see page 785. ADA-Funded Research

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    diabetic mice by unilateral intramuscular injection (2 × 105 cells/limb). Three weeks after the transplantation, current perception thresholds (CPTs), motor and sensory nerve conduction velocities (MNCV and SNCV, respectively), and plantar skin blood fl ow (PSBF) were evaluated.

    Results: FACS analysis showed that MLCs expressed CD44 and Sca-1, but not hematopoietic lineage markers. RT-PCR showed the expression of VEGF, FGF2 and NGF in MLCs. Three weeks after the transplantation, MLCs resided in hindlimb muscles. In 15-week diabetic mice (DM), CPTs in the saline- injected limbs were signifi cantly increased compared with these in normal mice (C), indicating hypoalgesia, and this deterioration was normalized in MLC-transplanted limbs. Decreased MNCV and SNCV in 15-week DM were signifi cantly ameliorated by MLC transplantation (MNCV; C: 44.5 ± 5.2m/s, DM: 34.4 ± 3.2, DM + MLCs: 38.6 ± 2.2, SNCV; C: 38.4 ± 6.8, DM: 26.0 ± 2.7, DM + MLCs: 31.1 ± 6.7). PSBF in 15-week DM was signifi cantly decreased compared with that in normal mice, which was signifi cantly ameliorated by MLC transplantation.

    Conclusions: These results suggest that MLC transplantation could have therapeutic effects on DPN through secreting angiogenic and neurotrophic factors.

    COMPLICATIONS—OCULAR

    390-PP Liver X Receptor Agonist Prevents Endothelial Progenitor Cell (EPC) Dysfunction and Diabetic Retinopathy (DR) MARIA B. GRANT, ASHAY BHATWADEKAR, SUGATA HAZRA, YUANQING YAN, MAKOTO MIYAZAKI, AMRISHA VERMA, XIAOXIN WANG, QIUHONG LI, MOSHE LEVI, Gainesville, FL, Denver, CO

    Liver X receptors (LXRs), of the nuclear receptor superfamily of ligand- activated transcription factors, are regulators of cholesterol homeostasis, modulate macrophage function and have potent anti-infl ammatory effects by inhibiting NF-κB, inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (Cox-2), interleukin-6 (IL-6), IL-1β, monocyte chemoattractant protein-1 and 3 (MCP-1 and MCP-3) and metalloprotease MMP-9. We hypothesized that LXR agonists could correct diabetes induced dysfunction of EPCs to protect against development of the vasodegenerative phase of DR. Diabetic mice, Db/db and STZ treated DBA/2J, or wild type mice were administered 10 mg/ kg (orally) of the LXR agonist, GW 3965, daily for 4 months. Mice were then sacrifi ced and retina and bone marrow were isolated. Lin-Sca1+, c-kit+ (LSK) cells from bone marrow were analyzed for migration and for components of renin angiotensin system (RAS), iNOS, and infl ammatory cytokines by qRT- PCR. Retinas were evaluated for number of acellular capillaries and GFAP immunoreactivity. EPCs of diabetic mice treated with GW3965 showed a signifi cant increase (p

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