Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Pennsylvania School of Medicine, 700 Clinical Research Building, 415 Curie Boulevard, Philadelphia, Pennsylvania 19104-6149, USA.
Glucose-dependent insulin secretion is often impaired after islet transplantation where reduced beta-cell secretory capacity indicates a low functional beta-cell mass.
We sought to determine whether glucagon-like peptide-1 (GLP-1) enhanced glucose-dependent insulin secretion and glucagon suppression in islet recipients, and whether GLP-1 effects were dependent on functional beta-cell mass by simultaneously studying recipients of whole pancreas transplants.
The study was performed in a clinical and translational research center.
Five intraportal islet and six portally drained pancreas transplant recipients participated in the study.
Subjects underwent glucose-potentiated arginine testing with GLP-1 (1.5 pmol . kg(-1) . min(-1)) or placebo infused on alternate randomized occasions, with 5 g arginine injected under basal and hyperglycemic clamp conditions.
Basal glucose was lower with increases in insulin and decreases in glucagon during GLP-1 vs. placebo in both groups. During the hyperglycemic clamp, a significantly greater glucose infusion rate was required with GLP-1 vs. placebo in both groups (P < 0.05), an effect more pronounced in the pancreas vs. islet group (P < 0.01). The increased glucose infusion rate was associated with significant increases in second-phase insulin secretion in both groups (P < 0.05) that also tended to be greater in the pancreas vs. islet group (P = 0.08), whereas glucagon was equivalently suppressed by the hyperglycemic clamp during GLP-1 and placebo infusions in both groups. The GLP-1-induced increase in second-phase insulin correlated with the beta-cell secretory capacity (P < 0.001). The proinsulin secretory ratio (PISR) during glucose-potentiated arginine was significantly greater with GLP-1 vs. placebo infusion in both groups (P < 0.05).
GLP-1 induced enhancement of glucose-dependent insulin secretion, but not glucagon suppression, in islet and pancreas transplant recipients, an effect dependent on the functional beta-cell mass that may be associated with depletion of mature beta-cell secretory granules.
"The biggest obstacle in islet transplantation is limited supply of donor islets, thus great efforts have been directed at strategies of " pure " β-cell replacement derived from stem cells (Ramiya et al., 2000) or surrogates (Newgard, 1994)—the panacea of the " cure " for diabetes! Of note, not only β-cell but also α-cell mass in transplanted islets are reduced, with surviving α-cells suffering from defective response to glucose and incretin hormone glucagon-like peptide-1 (GLP-1) (Newgard, 1994; Gupta et al., 1997; Paty et al., 2002; Zhou et al., 2008; Rickels et al., 2009). "
[Show abstract][Hide abstract] ABSTRACT: Normal release of glucagon from pancreatic islet α-cells promotes glucose mobilization, which counteracts the hypoglycemic actions of insulin, thereby ensuring glucose homeostasis. In treatment of diabetes aimed at rigorously reducing hyperglycemia to avoid chronic complications, the resulting hypoglycemia triggering glucagon release from α-cells is frequently impaired, with ensuing hypoglycemic complications. This review integrates the physiology of glucagon secretion regulating glucose homeostasis in vivo to single α-cell signaling, and how both become perturbed in diabetes. α-cells within the social milieu of the islet micro-organ are regulated not only by intrinsic signaling events but also by paracrine regulation, particularly by adjacent insulin-secreting β-cells and somatostatin-secreting δ-cells. We discuss the intrinsic α-cell signaling events, including glucose sensing and ion channel regulation leading to glucagon secretion. We then discuss the complex crosstalk between the islet cells and the breakdown of this crosstalk in diabetes contributing to the dysregulated glucagon secretion. Whereas, there are many secretory products released by β- and δ-cells that become deficient or excess in diabetes, we discuss the major ones, including the better known insulin and lesser known somatostatin, which act as putative paracrine on/off switches that very finely regulate α-cell secretory responses in health and diabetes. Of note in several type 1 diabetes (T1D) rodent models, blockade of excess somatostatin actions on α-cell could normalize glucagon secretion sufficient to attain normoglycemia in response to hypoglycemic assaults. There has been slow progress in fully elucidating the pathophysiology of the α-cell in diabetes because of the small number of α-cells within an islet and the islet mass becomes severely reduced and inflamed in diabetes. These limitations are just now being surmounted by new approaches.
Frontiers in Physiology 09/2012; 3:349. DOI:10.3389/fphys.2012.00349 · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Tightening of the diabetes control criteria in the last few years induces searches for adjunctive drugs to reinforce the basic treatment typical for the specific type of the disease. These agents are meant to stimulate insulin secretion, increase insulin sensitivity or inhibit the antagonists of the hormone. Up till now that kind of studies included adults, mainly with type 2 diabetes. Nowadays, however, the increasing number of research focuses on type 1 diabetic patients. The attempts to introduce this type of treatment in adolescent patients encounter many limitations, mostly of formal nature due to drug registration requirements. Nevertheless, more and more studies point at the efficacy of these agents and the possibility of their usage also in adolescents with different types of diabetes.
[Show abstract][Hide abstract] ABSTRACT: The explosion in the prevalence of diabetes mellitus has expanded beyond the Western world into Asian countries such as China.
Given the complication of diabetes, this expanding prevalence carries an attendant medical, social and financial burden for
countries with afflicted populations. Central to the pathogenesis of diabetes mellitus is a state of insulin insufficiency,
either absolute in the case of type 1 (T1DM) or relative in the case of type 2 (T2DM). The administration of exogenous insulin
contributes to the management of T2DM, and has become the mainstay of treatment in T1DM. However, this therapy brings with
it a substantial social and lifestyle impact. It is in this context that recent success in the islet transplantation field
offers promise for diabetic patients. A lack of availability of human donor islets for transplantation, however, hampers the
development and implementation of such novel therapeutic strategies. A new source of such cells must be identified and, in
this context, the induction of either embryonic or somatic stem cell differentiation into islet cells offers hope. Embryonic
stem cells (ESCs) display features suggesting that their differentiation into pancreatic insulin-producing cells may be possible.
However, the true origin of insulin release from these cells is uncertain, and it remains a concern that such cells may have
tumorigenic properties. Stem cells derived from the pancreas itself, however, might offer an exciting alternative. That such
cells exist suggests that the endocrine pancreas is capable of regeneration long into adulthood. The potential use of pancreatic
stem cells (PSCs) as a source of mature islet cells has recently been fuelled by the demonstration that such cells may be
induced to differentiate into islet-like cell clusters (ICCs). Nevertheless, these putative islets have so far failed to achieve
Advances in Experimental Medicine and Biology 01/2010; 690:155-77. DOI:10.1007/978-90-481-9060-7_9 · 1.96 Impact Factor
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