The hormone secreting islets of Langerhans in the pancreas have a unique cyto-architecture that allows functional interrelationships between the different cell types.
Somatostatin is secreted by the delta cell and is an effective inhibitor of the insulin-secreting beta cell and the glucagon-secreting alpha cell.
According to a novel study from Sweden’s Karolinska Instiutet, published in the journal Nature Communications, the delta cell can thereby indirectly affect glucose homeostasis in health and disease.
Our results provide important insight into the activity of the delta cell in health and pre-diabetes and a possible mechanism for how somatostatin can so effectively exert its potent suppressive effects within the islet of Langerhans,” says senior author Professor Per-Olof Berggren of the Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet in Sweden, who is also a visiting professor at Lee Kong Chian School of Medicine, Singapore.
Most delta cells are elongated and have a well-defined cell soma and a filopodia-like structure.
Using in vivo optogenetics and high-speed Ca2+ imaging, Per-Olof Berggren and his colleagues show that these filopodia are dynamic structures that contain a secretory machinery, enabling the delta cell to reach large numbers of beta cells within the islet.
This provides for efficient regulation of beta cell activity and is modulated by endogenous IGF-1/VEGF-A signaling.
In pre-diabetes, delta cells undergo morphological changes that may be a compensation to maintain paracrine regulation of the beta cell.
“It has long been a mystery how delta cells so effectively regulate the function of alpha and beta cells, only constituting a minority among the hormone secreting cells,” says Per-Olof Berggren.
“These are fundamental data explaining an important structure/function relationship between delta cells and other hormone-secreting cells, and provides the basis for how delta cells, despite being in minority, can act as efficient modulators of glucose homeostasis.”
Our hypothesis is that glucokinase (GCK) is the primary glucose sensor in mammals and the sensor responsible for regulation of glucose homeostasis as schematically represented in Figure 1.
That the signals for decreasing blood glucose (insulin) and for increasing blood glucose (glucagon, epinephrine, and other counter regulatory hormones and transmitters) depend on a common glucose sensor greatly facilitates integration into a stable regulatory system.
In support of our hypothesis, we will systematically develop its scientific basis.
The steps involved are: (1) evidence leading to recognition of the problem (Introduction). (2a) Establishing a positive correlation between the presence (and activity) of GCK and glucose response by cells that contribute significantly to regulation of glucose homeostasis and (2b) establishing that cells which do not respond directly to changes in blood glucose have little or no GCK activity or role in glucose homeostasis. (2c)
Evaluating the special metabolic role of the liver which contains most of the body’s GCK activity. (3)
Establishing causality, e.g., that alterations in GCK activity directly and in predictable ways affect glucose homeostasis. (4)
Evaluate evidence that glucose homeostasis utilizes glucose sensors other than GCK. We have included our definitions of receptor and metabolic metabolite sensing in order to avoid the ambiguity that might otherwise arise.
The Special Role of Liver in Glucose Homostasis
Liver has many functions, both metabolic and regulatory, and these regulatory functions include release of hormones involved in regulating general nutrient status, such as FGF21 (Fisher and Maratos-Flier, 2016).
The nutrient responses of the liver are not specific to glucose, however, and have only secondary effects on glucose homeostasis. Our focus is on glucose homeostasis and GCK. In contrast to neurons and endocrine tissues, in liver GCK has a major metabolic role, removing glucose from the blood when the levels are above normal. The removed glucose is largely stored as glycogen or used for fat synthesis.
This not only helps to prevent postprandial hyperglycemia but also assures adequate liver glycogen stores to stabilize blood glucose levels between meals (Agius, 2016). Additional levels of regulation of GCK present in liver that are specific to its role in glucose homeostasis include: (1) it is inhibited by a liver specific protein, GCKRP, and (2) expression of the GCK gene is entirely dependent on insulin. GCKRP is a 65 kDa monomeric protein expressed in hepatocytes in three- to fourfold excess of GCK (mol/mol) and localized almost exclusively in hepatic cell nuclei.
Human GCKRP inhibits human GCK in a manner competitive with glucose as measured in vitro when all three components are at physiological concentrations (de la Iglesia et al., 2000; van Schaftingen and Veiga da Cunha, 2004; Zelent et al., 2014; Agius, 2016). Figure 3 schematically shows some of the factors that affect interaction of GCK with GCKRP and contribute to regulation of GCK activity in hepatocytes. This inhibition is increased by fructose-6-phosphate (F-6-P) and reversed by fructose-1-phosphate (F-1-P), the product of fructokinase C. During fasting GCKRP binds GCK, inactivating it, and the complex is sequestered in the cell nucleus. It can be released by glucose or F-1-P following feeding, depending on the nature of consumed carbohydrate.
Dissociation of GCK/GCKRP complex by glucose results when glucose binds to the substrate site of GCK but this effect of glucose does not require MgATP; i.e., glucose acts as a first messenger, inducing a structural change of GCK causing the dissociation of the complex. F-1-P, in contrast, dissociates the complex by binding to GCKRP at a specific sugar-phosphate binding site where it is competitive with F-6-P, which stabilizes the complex. Details of the molecular processes underlying nuclear sequestration and release of the proteins are complex and remain to be elucidated. Highly effective drugs (called GCKRP inhibitors or GCK/GCKRP disruptors) have been developed that dissociate the GCK/GCKRP complex and thereby stimulate hepatic glucose phosphorylation and this lowers blood sugar in diabetic animals (Ashton et al., 2014). It remains to be seen whether using these agents proves clinically useful in treatment of hyperglycemia syndromes in T2DM and T1DM.
The preceding paragraph illustrates that carbohydrate metabolism of liver occupies a unique position in the intricate control system that maintains glucose homeostasis in man. This role is clearly distinct from those of the various cells and organs comprising the endocrine and neuronal network that regulates blood glucose as characterized in earlier paragraphs.
First, it must be appreciated that the hepatic involvement in regulating carbohydrate metabolism is only one of many functions liver plays in maintaining general body health. These functions include production and secretion of bile, gluconeogenesis, biosynthesis of complex lipids, ureagenesis, and chemical detoxifications.
In order to carry out their role in monosaccaride metabolism, liver cells have a high capacity complement of glucokinase, fructokinase C, and galactokinase 1. These enzymes are responsible for differential clearance of the common dietary hexoses from portal blood, initiating their conversion into glycogen for storage.
This removal and storage is essential to glucose homeostasis and co-determines the postprandial blood sugar profile. One might be tempted to characterize liver as a hexose sensing organ/tissue because it contains sugar specific kinases that have suitable kinetic constants (S0.5 and Vmax values), are irreversible, and lack product inhibition. This meets a significant part of our definition of metabolic sensors. What distinguishes hepatocytes from cells of the endocrine-neuronal network is that expression of GCK in liver is absolutely insulin dependent and this expression is inhibited by glucagon.
This is in contrast to constitutive expression of GCK in prototypical glucose sensing cells as, for example, in the islets of Langerhans and brain. The liver has a unique and crucial role in glucose homeostasis due to its large metabolic and storage capacities, but this role is regulated by insulin and glucagon, not glucose per se. The physiological importance of liver in glucose homeostasis is further attested by the presence of an additional insulin independent glucose sensing mechanism, inhibition of glycogen phosphorylase a (Hers, 1987; Matschinsky, 1990). Glucose at physiological concentrations facilitates enzymatic conversion of phosphorylase a to phosphorylase b and this inhibits glycogenolysis, an effect synergistic with glucose stimulation of glycogen synthesis.
The crucial role of GCK in control of hepatic fuel metabolism was recently demonstrated using mouse models in which hepatic insulin response was specifically eliminated by knockout of two Akt isoenzymes essential for insulin signaling.
Akt double KO mice lack hepatic GCK, are hyperglycemic, hypolipidemic, and moderately ketotic but have very high serum insulin levels. Repairing the hepatic GCK deficiency by viral vector technology normalized the diabetic phenotype of double Akt knockout mouse (Titchenell et al., 2017).
The role of GCK in liver is metabolic, i.e., it is important to postprandial removal of glucose from blood and maintaining hepatic glycogen levels. Its “regulatory” role is to activate metabolic pathways that store or degrade the G-6-P formed (glycogen synthesis vs glycolysis). Ferre et al. (1996) generated transgenic mice expressing the phosphoenolpyruvate carboxykinase/glucokinase (PEPCK/GCK) chimeric gene to study whether expression of GCK in the liver of diabetic mice might prevent diabetes induced metabolic alterations.
In contrast to non-transgenic mice treated with streptozotocin, when mice with transgene were treated with streptozotocin their livers showed high levels of both GCK mRNA and activity.
The increase in GCK was associated with an increase in intracellular levels of glucose-6-phosphate and glycogen as well as increase in pyruvate kinase activity and lactate production.
In addition, in liver from streptozotocin-treated transgenic mice gluconeogenesis and ketogenesis were normalized.
Thus, glycolysis was induced while gluconeogenesis and ketogenesis were blocked in diabetic mice expressing GCK. This was associated with normalization of blood glucose, ketone bodies, triglycerides, and free fatty acids even in the absence of insulin.
Nissim et al. (2012) assessed the impact of activating GCK pharmacologically using isolated liver preparations of fed rats and perfusing them with 5 mM glucose and physiological concentrations of lactate, pyruvate and ammonia.
They demonstrated that the allosteric GCK activator Piragliatin markedly enhanced every metabolic pathway downstream of glucose-6-phosphate that they studied.
This included glycolysis, as indicated by a marked increase of lactate release and respiration associated with a clear increase in energy state, glycogen synthesis, lipogenesis and ureagenesis, apparently caused by increased levels of N-acetyl-glutamate, while inhibiting gluconeogenesis. These results attest to importance of GCK activity on hepatic intermediary metabolism. The study illustrates the biological significance of the GCK/GCKRP molecular complex as metabolic switch depicted in Figure 3.
More information: Rafael Arrojo e Drigo et al. Structural basis for delta cell paracrine regulation in pancreatic islets, Nature Communications(2019). DOI: 10.1038/s41467-019-11517-x
Journal information: Nature Communications
Provided by Karolinska Institutet