Insulin resistance is associated with the circulating free fatty acid (FFA) level and intracellular lipid content in muscle and liver. We investigated the effect of 2-wk diet and exercise therapy on total adiposity, circulating FFA, intracellular lipid content in muscle and liver, and peripheral insulin sensitivity. Type 2 diabetic patients were divided into a diet group (n = 7) and a diet plus exercise group (n = 7). We performed a hyperinsulinemic-euglycemic clamp study before and after treatment. Intramyocellular lipid (IMCL) in the tibialis anterior muscle and intrahepatic lipid (IHL) were evaluated by (1)H-magnetic resonance spectroscopy. Fasting FFA were not altered, and total body fat showed a slight, but significant, decrease in both groups after treatment. IMCL was decreased by 19%, and the glucose infusion rate was increased by 57% in the diet plus exercise group, whereas neither IMCL nor glucose infusion rate was significantly altered in the diet group. However, IHL showed a significant decrease in both groups. In summary, we found that 2 wk of diet and exercise decreased IMCL and increased muscle insulin-mediated glucose uptake, whereas diet with or without exercise decreased IHL. These effects were evident despite a small decrease in body fat and were observed independently of fasting FFA levels.
Aims/hypothesis Endothelial cells are considered to be essential for normal pancreatic beta cell function. However, there have been no reports showing their importance for beta cell function. Materials and methods Using mice with disrupted vascular endothelial growth factor-A gene specifically in beta cells, we investigated the relation between islet vascular structure and beta cell function. Results Mice with disrupted vascular endothelial growth factor-A gene specifically in beta cells had reduced islet vascular density with impaired formation of endothelial fenestration. While their fasting glucose and body weight were comparable with control mice, their glucose-and tolbutamide-induced rapid insulin release were impaired, thus resulting in glucose intolerance. On the other hand, glucose and KCl enhanced the levels of insulin secreted from islets isolated from these mice. In addition, the production of soluble N-ethylmaleimide-sensitive factor attachment protein receptors in the islets was increased. Insulin content and expression of insulin I and pancreas duodenum homeobox 1 mRNA in the islets were also increased. Conclusions/interpretation Our results indicate that an abnormal quality and quantity of blood vessels due to reduced expression of vascular endothelial growth factor-A in beta cells could be a cause of impaired insulin secretion without impairment of beta cell function.
Protein kinase C (PKC) is considered to modulate glucosestimulated insulin secretion. Pancreatic  cells express multiple isoforms of PKCs; however, the role of each isoform in glucosestimulated insulin secretion remains controversial. In this study we investigated the role of PKC␦, a major isoform expressed in pancreatic  cells on  cell function. Here, we showed that PKC␦ null mice manifested glucose intolerance with impaired insulin secretion. Insulin tolerance test showed no decrease in insulin sensitivity in PKC␦ null mice. Studies using islets isolated from these mice demonstrated decreased glucose-and KCl-stimulated insulin secretion. Perifusion studies indicated that mainly the second phase of insulin secretion was decreased. On the other hand, glucose-induced influx of Ca 2؉ into  cells was not altered. Immunohistochemistry using total internal reflection fluorescence microscopy and electron microscopic analysis showed an increased number of insulin granules close to the plasma membrane in  cells of PKC␦ null mice. Although PKC is thought to phosphorylate Munc18-1 and facilitate soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptors complex formation, the phosphorylation of Munc18-1 by glucose stimulation was decreased in islets of PKC␦ null mice. We conclude that PKC␦ plays a non-redundant role in glucosestimulated insulin secretion. The impaired insulin secretion in PKC␦ null mice is associated with reduced phosphorylation of Munc18-1.Altered regulation of insulin secretion is a common feature of type 2 diabetes mellitus, although the underlying mechanism is not fully understood. The mechanism of glucose-stimulated insulin secretion involves closure of ATP-sensitive potassium channels by increased levels of glucose metabolites followed by depolarization of the plasma membrane and increased influx of Ca 2ϩ via voltage-dependent gating of Ca 2ϩ channels. The resultant elevation of intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) triggers transport of insulin into the plasma membrane and exocytosis (1). Although the events involved in initiating glucose-stimulated insulin secretion are well studied, those of regulated exocytosis are considerably less clear, although it is reported that several molecules expressed in  cells play a crucial role in exocytosis (2).Various protein kinases are activated by downstream signals of glucose metabolism; however, their precise contribution to insulin secretion is not clear yet (3). Protein kinase C (PKC) 2 is one such protein kinase. Previous studies revealed that phorbol 12-myristate 13-acetate, which activates PKC, could trigger insulin secretion (4 -10). PKC is a serine/threonine kinase characterized by molecular structure and activation requirement. The isoforms consist of the conventional PKCs (␣, , and ␥), which are sensitive to Ca 2ϩ and diacylglycerol (DAG), novel PKCs (␦, ⑀, , and ), which are sensitive to DAG only, and atypical PKCs (, ), which do not respond to either Ca 2ϩ or DAG (11,12). The  cells express PKC␣ and -␦ as...
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