Glucose-dependent blood flow dynamics in murine pancreatic islets in vivo

Abstract

Pancreatic islets are highly vascularized and arranged so that regions containing ␤-cells are distinct from those containing other cell types. Although islet blood flow has been studied extensively, little is known about the dynamics of islet blood flow during hypoglycemia or hyperglycemia. To investigate changes in islet blood flow as a function of blood glucose level, we clamped blood glucose sequentially at hyperglycemic (ϳ300 mg/dl or 16.8 mM) and hypoglycemic (ϳ50 mg/dl or 2.8 mM) levels while simultaneously imaging intraislet blood flow in mouse models that express green fluorescent protein in the ␤-cells or yellow fluorescent protein in the ␣-cells. Using line scanning confocal microscopy, in vivo blood flow was assayed after intravenous injection of fluorescent dextran or sulforhodamine-labeled red blood cells. Regardless of the sequence of hypoglycemia and hyperglycemia, islet blood flow is faster during hyperglycemia, and apparent blood volume is greater during hyperglycemia than during hypoglycemia. However, there is no change in the order of perfusion of different islet endocrine cell types in hypoglycemia compared with hyperglycemia, with the islet core of ␤-cells usually perfused first. In contrast to the results in islets, there was no significant difference in flow rate in the exocrine pancreas during hyperglycemia compared with hypoglycemia. These results indicate that glucose differentially regulates blood flow in the pancreatic islet vasculature independently of blood flow in the rest of the pancreas.THE ISLETS OF LANGERHANS are highly vascularized miniorgans within the pancreas. Researchers have long observed an intimate relationship between pancreatic islets and their distinguished vasculature (7). The vessels within the islet are more numerous and more tortuous than vessels in the surrounding exocrine tissue (2, 4). These characteristics of islet vasculature are likely related to the islets' function of sensing and responding to changes in blood glucose. The morphology of the pancreatic islet is notable in that regions containing ␤-cells are distinct from those containing ␣-and ␦-cells (19). However, investigations of the physiological importance of this distinct cellular organization of the islet and its vasculature are limited (19,26,27).Prior studies have shown two predominant islet blood flow patterns in murine islets (6,18,23,25). The most common pattern is where the blood initially perfuses the islet core and then the islet perimeter (3,18,22,25). In the second pattern, blood flows from one side of the islet to the other side, and thus perfuses core and perimeter areas simultaneously (16,18). The majority of these experimental data, however, have been gathered irrespective of blood glucose levels. Thus, little is known about islet blood flow during different metabolic states or changes in blood glucose levels. Since it has been suggested that glucose and/or insulin levels affect blood flow (10), we examined the islet blood flow dynamics as a function of blood glucose level.To examine ...

Pancreatic perfusion and subsequent response to glucose in healthy individuals and patients with type 1 diabetes

“…It is therefore likely that the pancreatic perfusion increase observed in this study did not only reflect an islet blood flow increase, as seen in rodents [4,5], but may also have occurred as a result of general blood flow increase, caused by parasympathetic signalling through the vagal nerve [12]. In line with this, the absence of an increase in pancreatic perfusion in diabetic individuals may be explained by autonomic neuropathy or endothelial dysfunction [13], albeit the type 1 diabetic participants involved in this study were chosen based on good metabolic control and absence of known microvascular complications.…”

“…In previous investigations, pancreatic perfusion in individuals with type 1 diabetes has been shown either not to change or to have a tendency to decrease [2,7]. Experience from animal studies [4][5][6] is suggestive that the perfusion difference between insulin-deficient and healthy animals mainly reflects the islet vascular component. Direct studies of islet blood flow in humans cannot be performed, since the techniques currently available for use in animal studies are invasive and/or terminal [4,5].…”

“…Experience from animal studies [4][5][6] is suggestive that the perfusion difference between insulin-deficient and healthy animals mainly reflects the islet vascular component. Direct studies of islet blood flow in humans cannot be performed, since the techniques currently available for use in animal studies are invasive and/or terminal [4,5]. Pancreatic islets are dependent on the effective transport of oxygen to the tissue for glucose metabolism, and a high perfusion for their dispersal of insulin [5,8].…”

“…The perfusion difference between insulin-deficient and healthy animals mainly reflects the islet vascular component, i.e. the islet blood flow contribution [4][5][6]. Moreover, a 2-3 fold increase in islet blood flow after intravenous glucose administration, which facilitates the release and dispersal of insulin, is consistently seen in healthy rodents [4,5].…”

“…the islet blood flow contribution [4][5][6]. Moreover, a 2-3 fold increase in islet blood flow after intravenous glucose administration, which facilitates the release and dispersal of insulin, is consistently seen in healthy rodents [4,5]. In this study we set out to study pancreatic perfusion under basal conditions and its responsiveness to glucose in non-diabetic ('healthy') and type 1 diabetic individuals.…”