747-6 Myocardial Blood Flow in Aortic Regurgitation: Comparison of Global and Regional Blood Flow to Regional Wall Stresses

The impact of regional wall stress (WS) abnormalities on regional coronary flow (CBF) in aortic regurgitation (AR) is not known. However, the existence of such a relation is of potential importance since it might account in part for LV dysfunction and myocardial fibrosis seen in AR, and could suggest therapeutic strategies. We have previously developed and validated a method for calculating regional WS in the radial, circumferential and meridional directions from mid wall (MW) to apex (AP) and endocardium (ENDO) to epicardium (EPI) using a 4000 element model of the LV To define the relation of regional WS and CSF in AR, we applied our LV model in 5 normal (NL) and 4 AR rabbits in which regional CBF was measured using fluorescent microspheres. CBF and radial WS were as follows:CBF (ml/min/gm)Radial WS (×103dynes/cm2)MWAPMWAPNLEPI2.491.308329*ENDO2.090.74133133*AREPI1.821.82*8638*ENDO1.410.77*133133**=p<0.001 (EPI vs ENDO for CSF, EPI to ENDO gradient in AR vs NL for radial WS)Thus, in AR, transmural CBF distribution varies significantly at the apex, while this tendency is less marked and less consistent in NL. No discernable transmural variation was apparent elsewhere in either group. These differences paralleled inversely the transmural variations in radial WS in AR vs NL. In contrast, meridional WS and circumferential WS were uniformly and significantly higher in AR than NL at apex and base (all p < 0.001), a pattern which bore no relation to regional CSF pattern. Thus, regional radial WS influences regional transmural CBF pattern in AR. The importance of this relation to regional LV function and regional myocardial fibrosis in AR now must be assessed

Heterogeneity of proliferative markers in pancreatic β-cells of patients with severe hypoglycemia following Roux-en-Y gastric bypass.

Severe postprandial hypoglycemia with neuroglycopenia is an increasingly recognized, debilitating complication of Roux-en-Y gastric bypass (RYGB) surgery. Increased secretion of insulin and incretin hormones is implicated in its pathogenesis. Histopathologic examination of pancreas has demonstrated increased islet size and/or nuclear diameter in post-RYGB patients who underwent pancreatectomy for severe refractory hypoglycemia with neuroglycopenia (RYGB + NG). We aimed to determine whether β-cell proliferation or apoptosis is altered in RYGB + NG. We performed an observational study to analyze markers of proliferation, apoptosis, cell cycle, and transcription factor expression in pancreatic tissue from affected RYGB + NG patients (n = 12), normoglycemic patients undergoing pancreatic surgery for benign lesions (controls, n = 6), and individuals with hypoglycemia due to insulinoma (n = 52). Proliferative cell nuclear antigen (PCNA) expression was increased in insulin-positive cells in RYGB + NG patients (4.5-fold increase, p < 0.001 vs. controls) and correlated with β-cell mass. Ki-67 immunoreactivity was low in both RYGB + NG and controls, but did not differ between groups. Phospho-histone H3 levels did not differ between RYGB + NG and controls. PCNA and Ki-67 were both significantly lower in both controls and RYGB + NG than insulinomas. Markers of apoptosis and cell cycle (M30, p27, and p21) did not differ between groups. PDX1 and menin exhibited similar expression patterns, while FOXO1 appeared to be more cytosolic in RYGB + NG. Markers of proliferation are heterogeneous in patients with severe post-RYGB hypoglycemia. Increased β-cell proliferation in some individuals may contribute to increased β-cell mass observed in severely affected patients

Low-frequency variants in HMGA1 are not associated with type 2 diabetes risk.

It has recently been suggested that the low-frequency c.136-14_136-13insC variant in high-mobility group A1 (HMGA1) may strongly contribute to insulin resistance and type 2 diabetes risk. In our study, we attempted to confirm that HMGA1 is a novel type 2 diabetes locus in French Caucasians. The gene was sequenced in 368 type 2 diabetic case subjects with a family history of type 2 diabetes and 372 normoglycemic control subjects without a family history of type 2 diabetes. None of the 41 genetic variations identified were associated with type 2 diabetes. The lack of association between the c.136-14_136-13insC variant and type 2 diabetes was confirmed in an independent French group of 4,538 case subjects and 4,015 control subjects and in a large meta-analysis of 16,605 case subjects and 46,179 control subjects. Finally, this variant had no effects on metabolic traits and was not involved in variations of HMGA1 and insulin receptor (INSR) expressions. The c.136-14_136-13insC variant was not associated with type 2 diabetes in individuals of European descent. Our study emphasizes the need to analyze a large number of subjects to reliably assess the association of low-frequency variants with the disease

Intracellular insulin in human tumors: examples and implications

Insulin is one of the major metabolic hormones regulating glucose homeostasis in the organism and a key growth factor for normal and neoplastic cells. Work conducted primarily over the past 3 decades has unravelled the presence of insulin in human breast cancer tissues and, more recently, in human non-small cell lung carcinomas (NSCLC). These findings have suggested that intracellular insulin is involved in the development of these highly prevalent human tumors. A potential mechanism for such involvement is insulin's binding and inactivation of the retinoblastoma tumor suppressor protein (RB) which in turn is likely controlled by insulin-degrading enzyme (IDE). This model and its supporting data are collectively covered in this survey in order to provide further insight into insulin-driven oncogenesis and its reversal through future anticancer therapeutics

Intergenerational Transmission of Glucose Intolerance and Obesity by In Utero Undernutrition in Mice

OBJECTIVE—Low birth weight (LBW) is associated with increased risk of obesity, diabetes, and cardiovascular disease during adult life. Moreover, this programmed disease risk can progress to subsequent generations. We previously described a mouse model of LBW, produced by maternal caloric undernutrition (UN) during late gestation. LBW offspring (F1-UN generation) develop progressive obesity and impaired glucose tolerance (IGT) with aging. We aimed to determine whether such metabolic phenotypes can be transmitted to subsequent generations in an experimental model, even in the absence of altered nutrition during the second pregnancy