Nishizawa M, Nakabayashi H, Uehara K, Nakagawa A, Uchida K, Koya D. Intraportal GLP-1 stimulates insulin secretion predominantly through the hepatoportal-pancreatic vagal reflex pathways. Am J Physiol Endocrinol Metab 305: E376 -E387, 2013. First published May 28, 2013; doi:10.1152/ajpendo.00565.2012.-We previously reported that glucagon-like peptide-1 (GLP-1) appearance in the portal vein facilitates hepatic vagal afferent activity, and this further augments reflexively the pancreatic vagal efferents in anesthetized rats, suggesting a neuroincretin effect of GLP-1. To determine whether the GLP-1-induced vagal pathways lead to a neuronal-mediated component (NMC) of insulin secretion, we infused GLP-1 at a physiological or pharmacological dose (1 or 3 pmol·kg Ϫ1 ·min Ϫ1 , respectively) into the portal vein in conscious rats with selective hepatic vagotomy (Vagox) or sham operation (Sham). The experiments consisted of two sequential 10-min intraportal infusions (P1 and P2): glucose at a physiological rate (56 mol·kg Ϫ1 ·min Ϫ1 ) in P1 and the glucose plus GLP-1 or vehicle in P2. Under arterial isoglycemia across the groups, the physiological GLP-1 infusion in Sham augmented promptly and markedly arterial insulin levels, approximately twofold the levels in glucose alone infusion (P Ͻ 0.005), and insulin levels in Vagox diminished apparently (P Ͻ 0.05). Almost 60% of the GLP-1-induced insulin secretion (AUC) in Sham met the NMC, i.e., difference between insulin secretion in Sham and Vagox, (AUC 976 Ϯ 65 vs. 393 Ϯ 94 pmol·min/l, respectively, P Ͻ 0.005). Intraportal pharmacological GLP-1 infusion further augmented insulin secretion in both groups, but the NMC remained in 46% (NS; Sham vs. Vagox). In contrast, "isoglycemic" intravenous GLP-1 infusion (3 pmol·kg) evoked an equal insulin secretion in both groups. Thus, the present results indicate that GLP-1 appearing in the portal vein evokes a powerful neuronal-mediated insulinotropic effect, suggesting the neuroincretin effect.vagal hormone reception; hepatic vagotomy; glucose-induced earlyphase insulin secretion; unrestrained conscious rat THE CLEAR DIFFERENCE between insulin secretion(s) to an oral, and that to intravenous, glucose load under isoglycemia was first coined in 1964 (13, 29). As to the concept of the gut-toislet connections, the term "enteroinsular axis" was proposed by Unger and Eisentraut (48), referring particularly to the role of peptides of the gastrointestinal tract in the axis. Later, an augmentation of insulin secretion upon glucose ingestion by still-undefined alimentary factors in those times, in the term "incretin", was conceptualized under the term "incretin effect", postulating complex humoral and neural mechanisms in the effect (10). Since in vitro and in vivo glucose-dependent insulinotropic actions by two of the intestinal hormones, gastric inhibitory polypeptide (also called glucose-dependent insulinotropic polypeptide, GIP) and glucagon-like peptide-1 (GLP-1) have been recognized (see reviews, Refs. 4, 16), they have been listed as in...

OBJECTIVE -To assess the prognostic role of ambulatory 24-h pulse pressure (PP) on various vascular events in relatively young type 2 diabetic subjects under 60 years of age.RESEARCH DESIGN AND METHODS -In this prospective study, 237 type 2 diabetic subjects without any history of vascular complications were analyzed. After excluding 9 dropout subjects, 228 subjects (mean age, 46 years; 69% men; mean follow-up period, 100 months) entered the study.RESULTS -Distribution of 24-h PP for all subjects showed left skewed data, indicating that there may be a diabetic subgroup that had a wide PP. Therefore, further analysis was performed by stratifying the diabetic subjects by quartile of 24-h PP. Outcomes for the widest quartile (n ϭ 58; cut point ϭ 53.3 mmHg) was then compared with those from the other narrower quartiles (n ϭ 170). In the diabetic subjects with a wide PP, cardiovascular events occurred more frequently than those in the diabetic subjects with a narrow one (20.7 vs. 4.1%; P Ͻ 0.001), resulting in the significant difference in the cumulative incidence of cardiovascular events (P Ͻ 0.001, log-rank test), but not cerebrovascular events, between the two subgroups. The Cox model revealed that a wide 24-h PP at baseline independently predicted subsequent cardiovascular events but not cerebrovascular events. By contrast, only duration of diabetes was the risk factor for cerebrovascular events.CONCLUSIONS -This study showed that a wide 24-h PP is predictive for cardiovascular events in relatively young diabetic subjects. Diabetes Care 28:102-107, 2005T here is now increasing evidence that wide pulse pressure (PP), which is an indicator of large arterial stiffness, is an independent predictor for cardiovascular disease in elderly subjects with essential hypertension (1,2). A prognostic role for PP has been extended to an unselected general population, including relatively young aged (3,4) and normotensive subjects (5). Furthermore, the Atherosclerosis Risk in Communities study (6) and the Hoorn study (7) demonstrated that type 2 diabetic subjects have stiffer arteries than individuals with normal glucose tolerance, which was confirmed using ambulatory 24-h monitoring of PP by van Dijk et al. (8). Recently, Domanski et al. (9) and Miyagi et al. (10) pointed out that a cardiovascular risk in subjects with a wide PP increased with the presence of diabetes. On the other hand, previous studies suggest that in subjects with essential hypertension, ambulatory PP not only correlates with organ damage (11) but also independently predicts cardiovascular events more precisely than clinic PP does (12,13). However, there is little information concerning PP of relatively young type 2 diabetic subjects, and the predictive value of ambulatory 24-h PP among these subjects has not been previously reported.The aim of this present study was to assess a prognostic role of ambulatory 24-h PP on various vascular events in type 2 diabetic subjects Ͻ60 years of age.RESEARCH DESIGN AND METHODS -The blood pressure (BP) monitoring progra...

Abstract. Selective arterial calcium stimulation and hepatic venous sampling (ASVS) for insulin secretion is used as a diagnostic procedure in patients with insulinomas or adult nesidioblastosis. In some of those patients, severe hypoglycemia requiring urgent glucose administration occurs during the procedure. Such glucose administration, however, may affect the results and damage the validity of the test. We report two cases of hyperinsulinemic hypoglycemia, in which ASVS tests were successfully performed under hyperinsulinemic euglycemic glucose clamps. A 40-year-old male with nesidioblastosis developed continual severe hypoglycemia several years after a Billroth II-Braun gastrectomy, and continuous glucose infusion could not be stopped even during ASVS tests. A 9-year-old girl with an insulinoma that showed atypical hypovascularity on imaging examinations had ASVS tests under a glucose clamp for safety. Hyperinsulinemic (l100 µU/ml) euglycemic (l90 mg/dl) clamps were achieved by an artificial endocrine pancreas. The insulin analogue lispro was utilized for clamps and endogenous insulin was measured with an assay that does not cross-react with the analogue. Diagnostically significant responses (more than twofold) of insulin secretion were observed under hyperinsulinemic clamps in both cases. The use of the hyperinsulinemic glucose clamp technique during the ASVS test should be considered for maintaining the safety of some hypoglycemic patients.

The present prospective observational study was designed to assess the prevalence of hemodialysis in type 2 diabetic patients with an impairment of plasma aldosterone responsiveness to adrenocorticotropic hormone (ACTH). Sixty seven patients (43 men and 24 women) were selected. The inclusion criteria were age <65 years; presence of normoalbuminemia (serum albumin >3.6 g/dl); and absence of azotemia (serum creatinine ≤1.2 mg/dl in males, and ≤1.0 mg/dl in females). Soluble

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