Yu-Kyong Shin

Bitter taste receptors influence glucose homeostasis.

TAS1R- and TAS2R-type taste receptors are expressed in the gustatory system, where they detect sweet- and bitter-tasting stimuli, respectively. These receptors are also expressed in subsets of cells within the mammalian gastrointestinal tract, where they mediate nutrient assimilation and endocrine responses. For example, sweeteners stimulate taste receptors on the surface of gut enteroendocrine L cells to elicit an increase in intracellular Ca2+ and secretion of the incretin hormone glucagon-like peptide-1 (GLP-1), an important modulator of insulin biosynthesis and secretion. Because of the importance of taste receptors in the regulation of food intake and the alimentary responses to chemostimuli, we hypothesized that differences in taste receptor efficacy may impact glucose homeostasis. To address this issue, we initiated a candidate gene study within the Amish Family Diabetes Study and assessed the association of taste receptor variants with indicators of glucose dysregulation, including a diagnosis of type 2 diabetes mellitus and high levels of blood glucose and insulin during an oral glucose tolerance test. We report that a TAS2R haplotype is associated with altered glucose and insulin homeostasis. We also found that one SNP within this haplotype disrupts normal responses of a single receptor, TAS2R9, to its cognate ligands ofloxacin, procainamide and pirenzapine. Together, these findings suggest that a functionally compromised TAS2R receptor negatively impacts glucose homeostasis, providing an important link between alimentary chemosensation and metabolic disease.

Exogenous Glucose–Dependent Insulinotropic Polypeptide Worsens Post prandial Hyperglycemia in T ype 2 Diabetes

OBJECTIVE Glucose-dependent insulinotropic polypeptide (GIP), unlike glucagon-like peptide (GLP)-1, lacks glucose-lowering properties in patients with type 2 diabetes. We designed this study to elucidate the underlying pathophysiology. RESEARCH DESIGN AND METHODS Twenty-two insulin-naïve subjects with type 2 diabetes were given either synthetic human GIP (20 ng · kg−1 · min−1) or placebo (normal saline) over 180 min, starting with the first bite of a mixed meal (plus 1 g of acetaminophen) on two separate occasions. Frequent blood samples were obtained over 6 h to determine plasma GIP, GLP-1, glucose, insulin, glucagon, resistin, and acetaminophen levels. RESULTS Compared with placebo, GIP induced an early postprandial increase in insulin levels. Intriguingly, GIP also induced an early postprandial augmentation in glucagon, a significant elevation in late postprandial glucose, and a decrease in late postprandial GLP-1 levels. Resistin and acetaminophen levels were comparable in both interventions. By immunocytochemistry, GIP receptors were present on human and mouse α-cells. In αTC1 cell line, GIP induced an increase in intracellular cAMP and glucagon secretion. CONCLUSIONS GIP, given to achieve supraphysiological plasma levels, still had an early, short-lived insulinotropic effect in type 2 diabetes. However, with a concomitant increase in glucagon, the glucose-lowering effect was lost. GIP infusion further worsened hyperglycemia postprandially, most likely through its suppressive effect on GLP-1. These findings make it unlikely that GIP or GIP receptor agonists will be useful in treating the hyperglycemia of patients with type 2 diabetes.

Modulation of Taste Sensitivity by GLP-1 Signaling in Taste Buds

Modulation of sensory function can help animals adjust to a changing external and internal environment. Even so, mechanisms for modulating taste sensitivity are poorly understood. Using immunohistochemical, biochemical, and behavioral approaches, we found that the peptide hormone glucagon‐like peptide‐1 (GLP‐1) and its receptor (GLP‐1R) are expressed in mammalian taste buds. Furthermore, we found that GLP‐1 signaling plays an important role in the modulation of taste sensitivity: GLP‐1R knockout mice exhibit a dramatic reduction in sweet taste sensitivity as well as an enhanced sensitivity to umami‐tasting stimuli. Together, these findings suggest a novel paracrine mechanism for the hormonal modulation of taste function in mammals.

Cannabinoids Inhibit Insulin Receptor Signaling in Pancreatic β-Cells

OBJECTIVE Optimal glucose homeostasis requires exquisitely precise adaptation of the number of insulin-secreting β-cells in the islets of Langerhans. Insulin itself positively regulates β-cell proliferation in an autocrine manner through the insulin receptor (IR) signaling pathway. It is now coming to light that cannabinoid 1 receptor (CB1R) agonism/antagonism influences insulin action in insulin-sensitive tissues. However, the cells on which the CB1Rs are expressed and their function in islets have not been firmly established. We undertook the current study to investigate if intraislet endogenous cannabinoids (ECs) regulate β-cell proliferation and if they influence insulin action. RESEARCH DESIGN AND METHODS We measured EC production in isolated human and mouse islets and β-cell line in response to glucose and KCl. We evaluated human and mouse islets, several β-cell lines, and CB1R-null (CB1R−/−) mice for the presence of a fully functioning EC system. We investigated if ECs influence β-cell physiology through regulating insulin action and demonstrated the therapeutic potential of manipulation of the EC system in diabetic (db/db) mice. RESULTS ECs are generated within β-cells, which also express CB1Rs that are fully functioning when activated by ligands. Genetic and pharmacologic blockade of CB1R results in enhanced IR signaling through the insulin receptor substrate 2-AKT pathway in β-cells and leads to increased β-cell proliferation and mass. CB1R antagonism in db/db mice results in reduced blood glucose and increased β-cell proliferation and mass, coupled with enhanced IR signaling in β-cells. Furthermore, CB1R activation impedes insulin-stimulated IR autophosphorylation on β-cells in a Gαi-dependent manner. CONCLUSIONS These findings provide direct evidence for a functional interaction between CB1R and IR signaling involved in the regulation of β-cell proliferation and will serve as a basis for developing new therapeutic interventions to enhance β-cell function and proliferation in diabetes.

Ghrelin Is Produced in Taste Cells and Ghrelin Receptor Null Mice Show Reduced Taste Responsivity to Salty (NaCl) and Sour (Citric Acid) Tastants

BACKGROUND The gustatory system plays a critical role in determining food preferences, food intake and energy balance. The exact mechanisms that fine tune taste sensitivity are currently poorly defined, but it is clear that numerous factors such as efferent input and specific signal transduction cascades are involved. METHODOLOGY/PRINCIPAL FINDINGS Using immunohistochemical analyses, we show that ghrelin, a hormone classically considered to be an appetite-regulating hormone, is present within the taste buds of the tongue. Prepro-ghrelin, prohormone convertase 1/3 (PC 1/3), ghrelin, its cognate receptor (GHSR), and ghrelin-O-acyltransferase (GOAT , the enzyme that activates ghrelin) are expressed in Type I, II, III and IV taste cells of mouse taste buds. In addition, ghrelin and GHSR co-localize in the same taste cells, suggesting that ghrelin works in an autocrine manner in taste cells. To determine a role for ghrelin in modifying taste perception, we performed taste behavioral tests using GHSR null mice. GHSR null mice exhibited significantly reduced taste responsivity to sour (citric acid) and salty (sodium chloride) tastants. CONCLUSIONS/SIGNIFICANCE These findings suggest that ghrelin plays a local modulatory role in determining taste bud signaling and function and could be a novel mechanism for the modulation of salty and sour taste responsivity.

Vasoactive intestinal peptide-null mice demonstrate enhanced sweet taste preference, dysglycemia, and reduced taste bud leptin receptor expression.

OBJECTIVE It is becoming apparent that there is a strong link between taste perception and energy homeostasis. Recent evidence implicates gut-related hormones in taste perception, including glucagon-like peptide 1 and vasoactive intestinal peptide (VIP). We used VIP knockout mice to investigate VIPs specific role in taste perception and connection to energy regulation. RESEARCH DESIGN AND METHODS Body weight, food intake, and plasma levels of multiple energy-regulating hormones were measured and pancreatic morphology was determined. In addition, the immunocytochemical profile of taste cells and gustatory behavior were examined in wild-type and VIP knockout mice. RESULTS VIP knockout mice demonstrate elevated plasma glucose, insulin, and leptin levels, with no islet β-cell number/topography alteration. VIP and its receptors (VPAC1, VPAC2) were identified in type II taste cells of the taste bud, and VIP knockout mice exhibit enhanced taste preference to sweet tastants. VIP knockout mouse taste cells show a significant decrease in leptin receptor expression and elevated expression of glucagon-like peptide 1, which may explain sweet taste preference of VIP knockout mice. CONCLUSIONS This study suggests that the tongue can play a direct role in modulating energy intake to correct peripheral glycemic imbalances. In this way, we could view the tongue as a sensory mechanism that is bidirectionally regulated and thus forms a bridge between available foodstuffs and the intricate hormonal balance in the animal itself.

Predictive factors for nephritis, relapse, and significant proteinuria in childhood Henoch-Schonlein purpura

Objective: To identify predictive factors for nephritis, relapse, and significant proteinuria in childhood Henoch–Schönlein purpura (HSP). Methods: Two hundred and six consecutive patients with HSP (93 female, 113 male), followed up at a single centre between 1996 and 2001, were analysed retrospectively. They were regularly monitored for clinical and laboratory parameters for renal sequelae and relapse. Results: Nephritis was seen in 78 patients (38%), relapse in 52 (25%), and significant proteinuria in 39 (19%). In univariate analysis, an older age at onset (>10 years), persistent purpura, severe bowel angina, and relapse were identified as factors associated with nephritis and significant proteinuria. Relapse‐related factors were an older age, persistent purpura, severe bowel angina, and leucocytosis. Logistic regression analysis showed that nephritis was significantly associated with an older age, persistent purpura, and relapse, and significant proteinuria was closely related to severe bowel angina and relapse. Conclusion: We identified some predictors for nephritis, relapse, and significant proteinuria in childhood HSP, and close attention should be paid to those patients with the risk factors, such as an older age at onset, persistent purpura, severe bowel angina, and relapse.

Insulin and glucagon regulate pancreatic α-cell proliferation.

Type 2 diabetes mellitus (T2DM) results from insulin resistance and β-cell dysfunction, in the setting of hyperglucagonemia. Glucagon is a 29 amino acid peptide hormone, which is secreted from pancreatic α cells: excessively high circulating levels of glucagon lead to excessive hepatic glucose output. We investigated if α-cell numbers increase in T2DM and what factor (s) regulate α-cell turnover. Leprdb/Leprdb (db/db) mice were used as a T2DM model and αTC1 cells were used to study potential α-cell trophic factors. Here, we demonstrate that in db/db mice α-cell number and plasma glucagon levels increased as diabetes progressed. Insulin treatment (EC50 = 2 nM) of α cells significantly increased α-cell proliferation in a concentration-dependent manner compared to non-insulin-treated α cells. Insulin up-regulated α-cell proliferation through the IR/IRS2/AKT/mTOR signaling pathway, and increased insulin-mediated proliferation was prevented by pretreatment with rapamycin, a specific mTOR inhibitor. GcgR antagonism resulted in reduced rates of cell proliferation in αTC1 cells. In addition, blockade of GcgRs in db/db mice improved glucose homeostasis, lessened α-cell proliferation, and increased intra-islet insulin content in β cells in db/db mice. These studies illustrate that pancreatic α-cell proliferation increases as diabetes develops, resulting in elevated plasma glucagon levels, and both insulin and glucagon are trophic factors to α-cells. Our current findings suggest that new therapeutic strategies for the treatment of T2DM may include targeting α cells and glucagon.

Cannabinoids Induce Pancreatic β-Cell Death by Directly Inhibiting Insulin Receptor Activation

Activation of cannabinoid 1 receptors prevents insulin receptors from promoting β-cell survival in the pancreas. Death by Cannabinoids Cannabinoid receptors are located in the brain and in the periphery, where they mediate effects on mood, appetite, metabolism, and pain perception. In pancreatic β cells, cannabinoid 1 receptors inhibit insulin action. Kim et al. showed that cannabinoid 1 receptors also prevent prosurvival signaling through the insulin receptor by attenuating its activation. Because loss of β cells through cell death contributes to the decline in pancreatic function seen in both type 1 and type 2 diabetes, pharmacological blockade of the cannabinoid 1 receptor could be developed as a potential therapy for diabetes. Cannabinoid 1 (CB1) receptors have been previously detected in pancreatic β cells, where they attenuate insulin action. We now report that CB1 receptors form a heteromeric complex with insulin receptors and the heterotrimeric guanosine triphosphate–binding protein α subunit Gαi. Gαi inhibited the kinase activity of the insulin receptor in β cells by directly binding to the activation loop in the tyrosine kinase domain of the receptor. Consequently, phosphorylation of proapoptotic protein Bad was reduced and its apoptotic activity was stimulated, leading to β-cell death. Pharmacological blockade or genetic deficiency of CB1 receptors enhanced insulin receptor signaling after injury, leading to reduced blood glucose concentrations and activation of Bad, which increased β-cell survival. These findings provide direct evidence of physical and functional interactions between CB1 and insulin receptors and suggest a mechanism whereby peripherally acting CB1 receptor antagonists improve insulin action in insulin-sensitive tissues independent of the other metabolic effects of CB1 receptors.

Notch signaling in pancreatic endocrine cell and diabetes.

Recent studies have improved our understanding of the physiological function of Notch signaling pathway and now there is compelling evidence demonstrating that Notch is a key regulator of embryonic development and tissue homeostasis. Although further extensive studies are necessary to illustrate the molecular mechanisms, new insights into the role of Notch signaling in pancreas development and diabetes have been achieved. Importantly, the ability to regulate Notch signaling intensity both positively and negatively may have therapeutic relevance for diabetes. Thus, this paper reviews the current knowledge of the roles of Notch signaling in the pancreatic endocrine cell system.