Does the correction refer to the intracellular environment? at Insulin is really cool in that, its effect on the cell is to tell it to produce GLUT2 transporters so that it can take in glucose.

So both are necessary in order to uptake glucose. For the second question, remember that at cell membranes, there are two gradients at play that determine movement of solutes. There's an electrical gradient, and a chemical gradient. Comment Button navigates to signup page.

Posted 8 years ago. I'm confused about the potassium channel. Sal says potassium passively leaves the cell so at rest there's more potassium outside the cell but the correction says he meant "less", but how can there be less potassium outside the cell if potassium is passively leaving the cell?

Also, he says when there's ATP it prevents potassium from leaving the cell so the cell membrane becomes depolarized. How can it be depolarized if the cell is more positively charged than the outside to begin with, and it gets even more positively charged when there's ATP?

Under the resting condition, the potassium ions leave the cell through "leaky" open protein channels and will continue doing so as long as their concentration in the cell is higher than their concentration outside of the cell. This means that when potassium ions leave the cell, their concentration outside is less than inside of the cell.

Therefore, the correction to the video is accurate. As under the resting conditions there is a negative resting membrane potential around negative 50 to 70 mV , this leads to the cell membrane depolarization making it less negative.

the video shows where the glucose is going into the cell glut after some steps the calcium help the insulin to leave the cell right?

i thought the glucose cant get into the cell with out insulin. can you help me with this question please. Direct link to enxhi. How can the beta cells be polarized by facilitated diffusion? What drives the movement of potassium from inside the cell to outside the cell if it is going against it's concentration gradient?

Kiran Virani. How would the pancreas and liver respond to hypoglycaemia? Candace Lei. Hypoglycemia means your blood glucose level is way too lower than the normal level. In that case, the pancreas will secrete glucagon and signal the liver to carry out glycogenolysis breakdown of glycogen to glucose in order to raise the blood sugar level.

Noted gluconeogenesis is also promoted by increase level of glucagon, yet the liver will not go to that way unless your body is at a fasting state. Tommy Tang. Is there any more detail on how alpha cells release glucagon?

Or do we only have discovered amino acids trigger glucagon release? Cody Weiler. why do they say in their edit that potassium is higher inside the cell compared to outside. Isn't potassium always leaving at rest making it higher outside compared to inside? Video transcript - [Voiceover] As you can see on this gentleman right here, he's got a liver, and then this organ down here is referred to as the pancreas.

Now the pancreas sits in the retroperitoneum which relative to the liver, which sits in the peritoneum, or in the abdomen, the pancreas is found to the back and to the left, to the back and to the left.

And what's distinctive about the pancreas is it's blood supply. And so we can go through that in a little more detail after I blow up the pancreas right here and move it over just a little bit. Now the pancreas is like most organs, in that it receives oxygen rich arterial blood flow and gives off oxygen poor blood flow through the venous system.

So this is the venous blood right here. And this is the arterial blood. But in addition to these two things, the pancreas also receives blood flow from the intestine, which I can draw right here.

The small intestine will deliver unique nutrient rich blood through the pancreas and this is nutrient rich blood through the portal venous system. This is the portal venous blood flow.

And once this nutrient rich blood flows through the pancreas it will trigger hormone release. Hormones such as insulin and glucagon and that'll actually be released into the portal venous blood and travel along with the rest of the nutrients to the liver.

And the cool thing about the hormones going straight to the liver first means that the effects they have there are four times greater than what you will see in the rest of the body. So insulin and glucagon from the pancreas will have four times greater effect in the liver than in the rest of the body.

But now the thing about the pancreas is that it doesn't just contain insulin and glucagon hanging out in random cells, they're organized. So if we blow up a small part of the pancreas right over here, we would see this. Which is a collection of cells here, like an island, surrounded by other cells.

These other cells on the outside secrete enzymes that go into the GI tract, and we won't worry too much about them now, but the cells here in this island are referred to as the islet of langerhans. So it's the islet of langerhans. Which is just a fancy term for an island of cells.

And the way the cells are organized in here is very structured. You'll have what are called beta cells in the middle of the island and on the outside you'll have what are called alpha cells. So alpha cells on the outside. And the key thing to remember here is that your beta cells release insulin while the alpha cells release glucagon.

The alpha cells release glucagon. And we can actually go into further detail about how beta cells, for instance, secrete insulin into the blood. Let's start by focusing on this beta cell right here. I'll be sure to label this. This is a beta cell right here. This is our beta cell and these guys store insulin.

So I'll write insulin here in this secretory vesicle. And I'll show you how it's released into the blood stream. This secretory vesicle, much like many secretory vesicles in the body, will release their contents outside of the cell if there's calcium present.

So I'll put this calcium receptor here for now. The other thing that's unique about beta cells is that they have these potassium channels. So potassium channels that allow potassium to leave beta cells through facilitated diffusion.

So they're just naturally leaving the beta cell over time. Which means that at rest there's a lot more potassium ions living outside of the beta cell than there are inside of the beta cell. And that's an important distinction because that's how we prevent the beta cell from being depolarized or getting a more positive charge within the cell.

However, APRP was demonstrated to have neither ecdysiotropic effects in L. migratoria , nor to influence the ecdysteroid-dependent timing of developmental transitions in D. melanogaster De Loof et al. The CC receives both extrinsic and intrinsic regulatory inputs.

An AKH-mediated autocrine feedback loop negatively regulates akh expression Gàlikovà et al. Nutrition directly influences CC glucose metabolism in a manner that regulates cell membrane electrical activity; this is discussed thoroughly in the next section of this review.

Other nutrient-derived factors include: the muscle-derived cytokine unpaired-2 Upd2 that alters AKH secretion Zhao and Karpac, ; α-bursicon is secreted from enteroendocrine cells and signals through Dlgr2 to negatively regulate AKH production and systemic signaling Scopelitti et al.

Additionally, the gustatory water-sensing ion channel pickpocket28 ppk28 negatively regulates AKH secretion Waterson et al. These and other factors that provide regulatory input to the CC are reviewed elsewhere Nässel and Winther, ; Ahmad et al.

The physiological effects of AKH are mediated by the D. melanogaster AKH receptor DAKHR; also AKHR. melanogaster AkhR is the first insect AkhR gene reported to encode a seven-transmembrane domain G-protein coupled receptor, or GPCR Staubli et al.

AKHR is structurally- and evolutionarily-related to the mammalian gonadotropin-releasing hormone GnRH receptor, and was named originally named GnRHR Staubli et al. When the ligand of the D. melanogaster GnRHR was identified as AKH, this receptor was renamed AKHR Staubli et al. AKHR will be discussed further below.

In situ localization of AkhR expression and AKHR protein abundance within the fly is complicated by the difficulty in distinguishing between highly conserved regions of GPCRs.

Reporter gene expression driven by AkhR -GAL4 in adults suggests that AkhR is expressed in the fat body tissues of the head and abdomen Bharucha et al. AkhR -GAL4 also drives expression in the sweet sensing gustatory receptor neurons of the suboesophageal ganglion SOG Bharucha et al.

These AkhR -GAL4-driven expression patterns are not comprehensive. Tissue-specific expression of AkhR -RNAi also identified roles for AKHR signaling in the IPCs, the PG, and in four interoceptive SOG neurons ISNs Kim and Neufeld, ; Jourjine et al.

Eight DILPs are produced in Drosophila and their expression patterns and functions vary according to discrete stages of life; this information is thoroughly reviewed elsewhere Owusu-Ansah and Perrimon, ; Nässel and Vanden Broeck, The regulation of DILP biosynthesis, secretion, and signaling in Drosophila is very complex, and only a brief summary can be provided here.

Insulin signaling in Drosophila is more complex than in mammals, and it is inappropriate to generalize all DILPs as being direct actors in metabolic homeostasis in the same sense that β cell-derived insulin is in mammals.

It is similarly inappropriate to oversimplify the activities of AKH and all DILPs as being antagonistic. However, specific DILPs do directly alter haemolymph glucose titers e. Adipokinetic hormone and DILP secretion must be coordinated so that their antagonistic actions preserve hemolymph glucose homeostasis.

Central to this goal is the ability of the CC and IPCs to monitor energy homeostasis through cell autonomous nutrient sensing of circulating glucose titers.

This is accomplished by the evolutionarily conserved K ATP channels. ATP-Sensitive Potassium channels function as cell autonomous nutrient sensors in mammalian pancreatic α and β cells for comprehensive reviews, see: Ashcroft and Rorsman, ; Rorsman et al. melanogaster larval and adult CC; these channels are also present in the adult—but not larval—IPCs Kim and Rulifson, ; Fridell et al.

K ATP channels also contribute to healthy mammalian and Drosophila cardiac function Akasaka et al. The K ATP channel contains two subunits comprised of four regulatory sulfonylurea receptors SURx: SUR1 in mammals; Sur in flies and four pore-forming weakly inward rectifying potassium channels Kir6.

x: Kir6. x bears an ATP-binding domain and SURx bears a Mg-ADP-binding domain: Kir6. x-ATP binding stimulates channel closure and cell membrane depolarization; SURx-Mg-ADP stimulates channel opening and cell membrane polarization.

The weakly inward rectifying action of the Kir6. Glucose transporters bring glucose into the mouse α GLUT1 and GLUT4 and β GLUT2 cells where it enters the Krebs cycle for ATP production Heimberg et al.

This stimulates cell membrane depolarization and—along with an unidentified depolarizing current—causes action potential firing that regulates insulin and glucagon secretion Rorsman et al.

Paradoxically, K ATP channel closure causes depolarization and action potential firing in both cell types but promotes insulin secretion from β cells while inhibiting glucagon secretion from α cells.

The means whereby α and β cell K ATP channels produce opposite effects on secretion in response to the same glucose titers is still incompletely understood.

Recent work demonstrated that this is likely due to differential glucose sensitivity of K ATP channels between the two cell types, which significantly alters cellular excitability and action potential firing Göpel et al.

I will review electrical regulation of both α and β cells in order to contrast important differences in effect of K ATP channel activity between the two cell types.

Insulin secretion from β cells is stimulated by cell membrane depolarization caused by K ATP channel closure Cook and Hales, ; Rorsman et al. β cell K ATP channel conductance is high i. Electrical regulation of insulin secretion from β cells is thoroughly reviewed elsewhere Sarmiento et al.

α cells are more sensitive to glucose than are β cells. In contrast to β cells, α cells show very low K ATP channel conductance at 1 mM of glucose; this results from α cell K ATP channels having a 5-fold greater sensitivity to ATP produced by glucose phosphorylation Zhang et al.

As a result, small changes in K ATP channel activity i. The high sensitivity of these K ATP channels is crucial as it makes α cells electrically active at low glucose concentrations, thus stimulating VGCC activity and permitting glucagon secretion at glucose concentrations that inhibit insulin secretion from β cells.

The crucial role played by voltage-gated sodium channels VGSCs in mediating this process in α cells that is described below. Just as importantly—because glucagon must be secreted only during hypoglycemia—increasing glucose concentrations to 6 mM rapidly closes all remaining α cell K ATP channels.

This produces strong membrane depolarization and action potential firing, and—through the activity of VGSCs—prevents glucagon secretion during hyperglycemia. Glucagon secretion is thus both stimulated and inhibited by varying magnitudes of K ATP channel activation.

This relation between K ATP channel conductance and glucagon secretion follows an inverted U-shaped dose response curve where maximum secretion occurs at 1 mM glucose, and small increases or decreases in conductance inhibit secretion Zhang et al.

α cell membranes bear VGSCs that are activated by K ATP channel closure and membrane depolarization at 1 mM glucose. The VGSCs produce rapid and short-lived amplification of the moderate depolarizing stimulus that is produced by K ATP channel closure at low glucose concentrations.

When all α cell K ATP channels close in response to hyperglycemia, further membrane depolarization increases action potential firing and inactivates VGSCs. VGSC closure reduces action potential firing and spike height, VGCCs are subsequently inactivated, and glucagon secretion is inhibited.

The precise regulation of ion channel activity through K ATP channel-mediated nutrient sensing underlies the proper timing of glucagon and insulin secretion. Homeostatic control of blood glucose homeostasis is highly sensitive to any factors that dysregulate channel function.

Mutations in K ATP channels, VGCCs, and VGSCs that perturb their function are currently the focus of research aimed at identifying causal mechanisms that underlie the pathogenesis of diabetes.

The precise mechanism whereby α cell membrane electrical activity and glucagon secretion are regulated remains to be elucidated.

Although glucose-dependent K ATP channel activity certainly plays a prominent role in regulating the inverted U-shaped curve of α cell membrane electrical activity described above, it is not the sole determinant of glucagon secretion.

Evidence suggests that K ATP channel-independent mechanisms can contribute to this pattern of electrical activity and produce glucagonostatic effects at high glucose concentrations through both extrinsic paracrine and intrinsic means.

In β cells, insulin secretion is inhibited by AMPK and stimulated by PKG Granot et al. This is mediated by mechanisms that are both dependent and independent of AMPK.

Liver kinase B1 LKB1 induces AMPK activity to inhibit insulin biosynthesis and secretion in both a glucose- and amino acid-responsive manner da Silva Xavier et al. AMPK also inhibits insulin secretion via a leptin-mediated feedback loop Tsubai et al. In response to feeding, insulin promotes leptin secretion from adipose tissue, and leptin signaling in β cells subsequently induces protein kinase A PKA activation of AMPK Park et al.

Leptin-PKA-AMPK signaling regulates membrane polarity—and thus cell excitability—by promoting K ATP channel trafficking to the β cell membrane Cochrane et al. This increases K ATP channel conductance and hyperpolarizes the cell membrane.

Importantly, this occurs only in a progressively fasted state when the glucose:leptin titer ratio decreases to a level where continued insulin secretion would produce a hypoglycemic state Park et al.

In β cells, PKG promotes insulin secretion in a fed state either by phosphorylating and closing K ATP channels or by phosphorylation of proteins that indirectly target K ATP channels Soria et al.

PKG activity is induced by atrial natriuretic peptide ANP signaling in β cells Undank et al. PKA also phosphorylates and closes K ATP channels, and PKG promotes this inhibitory effect by preventing phosphodiesterase deactivation of PKA Undank et al.

This PKA-mediated increase in insulin secretion appears contradictory to its inhibitory effect reported above; however, PKA inhibition of K ATP channels is mediated by PKG signaling, whereas leptin-PKA-AMPK signaling increases K ATP channel conductance in the absence of PKG activity Undank et al. The complexity of the glucose-responsive and self-regulatory pathways present in β cells reflects the need for rapid responses in insulin secretion to changes in blood glucose levels.

This promotes glucagon secretion through an incompletely characterized signaling cascade Leclerc et al. Induction of AMPK by AMP is mediated by LKB1 during hypoglycemia, but AMPK is not the sole target of LKB1 phosphorylation in glucagon regulation Sun et al.

This physiological effect suggests that—as in β cells—PKG might phosphorylate VGCCs and close these channels. Further insight is provided by research into cardiac myocytes where nitric oxide stimulated PKG activity inhibits Ca v 1.

The murine research reviewed above informs future research into the regulatory mechanisms of AKH secretion in D. Endocrine research requires the ability to quantify changes in hormone secretion.

However, circulating AKH titers in D. melanogaster are estimated to be in the low femtomolar range, and this makes the reliable quantification of AKH titers an ongoing challenge that will be addressed below Isabel et al. Pharmacological and transgenic manipulations were used to implicate K ATP channels in the regulation of AKH secretion from the larval CC Kim and Rulifson, Tolbutamide is a diabetic drug that targets the Sur subunits of K ATP channels.

Tolbutamide treatment was used in conjunction with transgenic manipulations where the CC was ablated to show that the increase in glucose titers was dependent upon the CC.

The effect of tolbutamide was inhibited when CC membrane depolarization was transgenically inhibited. These experiments provided strong evidence for the existence of K ATP channels in the CC and for their regulatory role in AKH secretion Kim and Rulifson, Adult IPCs bear K ATP channels, and in vivo electrophysiological measurements of these cells were used to discern the influence of K ATP channels on membrane potential; the potential for applying this technique to the CC has not been explored Fridell et al.

A major contribution to the characterization of mechanisms that regulate CC cell membrane potential and AKH secretion was recently reported Perry et al. Three genes that encode components of K ATP channels Sur , calcium channels Ca-Beta , and potassium channels sei were identified through RNAi-mediated knockdown as regulatory candidates for excitation-secretion coupling for AKH in the CC.

These results provided further support for the nutrient-sensing role of K ATP channels in the CC. The identification of CC ion channel components greatly improves the utility of D. melanogaster as a model for α cell dysregulation, hyperglucagonemia, and the pathogenesis of T2DM.

The murine cGKI research described above prompted the hypothesis that PKG—encoded by dg2 in D. melanogaster —might negatively regulate AKH secretion. Reduced dg2 expression in the larval CC reduced intracellular AKH abundance, and this correlated with a low nutrient-dependent developmental delay and increased lethality prior to pupariation Hughson et al.

Compared to control genotypes, more of these larvae survived pupal metamorphosis and developed into adults with greater starvation resistance and increased body size to lipid content ratio, a trait associated with obesity in humans.

This suggested that dg2 functioned in the CC to increase survival during larval development in a low nutrient environment, and but that this resulted in a tradeoff with starvation resistance during adult life Hughson et al.

Further research demonstrated that dg2 also influenced AKH abundance in the adult CC Hughson, in press. Reduced dg2 expression in the adult CC decreased intracellular AKH, but—in contrast to larvae—correlated with decreased body size to lipid content ratio.

This effect correlated with evidence of increased systemic lipid catabolism and reduced starvation resistance during adult life. As described above, the CC is developmentally orthologous to the mammalian anterior pituitary gland Wang et al.

The PI location of IPCs of the fly protocerebrum is orthologous to the mammalian hypothalamus Wang et al. Although there is little conservation between AKH and glucagon amino acid sequences, both hormones act through the same evolutionarily conserved signaling pathway to regulate transcriptional responses to hypoglycemia De Loof and Schoofs, ; Clynen et al.

The HP axis also regulates the time of onset of puberty. When the HP axis detects a minimum level of body growth during childhood it stimulates steroid hormone biosynthesis in the gonads Shalitin and Philip, The subsequent rise in steroid titers initiates the developmental transition from sexual immaturity to maturity.

Paracrine signaling between the hypothalamus and pituitary gland is mediated by GnRH, which stimulates the secretion of gonadotropins that enter circulation and stimulate steroid hormone biosynthesis and secretion from the gonads.

melanogaster , steroid hormones similarly regulate the timing of this developmental transition. The evolutionary relatedness of GnRHR and AKHR was introduced above. The conservation of AKHR and GnRHR prompted the hypotheses that AKHR influenced development by regulating ecydsteroidogenesis, and that AKH—in addition to its glucagon-like properties—possessed dual functionality as both a glucagon-like and GnRH-like peptide.

Conserved peptide sequences between AKH and GnRH seemed to provide support for this hypothesis Lindemans et al. However, recent work investigating AKH and AKHR loss of function mutant lines demonstrated that neither AKH nor AKHR affected developmental i.

While development was not altered in AKH loss of function mutants, recent work identified the possibility that AKH might play a role in ecdysteroid biosynthesis in the PG. Evidence comes from work demonstrating a role for AKH-regulated hormone sensitive lipase HSL activity in steryl ester metabolism and the intergenerational transfer of sterols Heier et al.

This pathway regulates catabolism of steryl ester lipid droplet stores and plays an essential role in ecdysteroid biosynthesis. While this work reported no effect of an HSL loss of function mutation on PG lipid droplets, these data came from animals reared in a lipid- and sterol-abundant feeding environment and larval development was not reported.

The possibility that this pathway influences ecdysteroid biosynthesis in sterol-limited or -deficient environments needs to be explored. This avenue of research is supported by a developmental role for AKH that was observed only in low nutrient conditions Hughson et al.

Larvae reared in a low nutrient i. This gene, dg2 , is orthologous to cGKI, which encodes the PKG that regulates alpha cell membrane excitability Leiss et al.

This delay was AKH-dependent, and—as observed in AKH mutants reared in nutrient-abundant conditions—was absent in nutrient-abundant conditions Gàlikovà et al. This trait was associated with GPCR-mediated active secretion of ecdysteroids from the PG as well as with AKH activation of the HSL pathway Yamanaka et al.

It is vital to reemphasize that AKH mutants did not exhibit developmental defects, delays, or fitness consequences, and that this definitively demonstrated that AKH is not essential for development in a nutrient-abundant environment Gàlikovà et al. There is no contradiction between this seminal work and the report of an AKH-dependent effect on developmental timing that was present only in low nutrient conditions Hughson et al.

Instead, this identifies the possibility that in challenging nutritional environments AKH can play a non-essential role in development in a manner fitting for a stress peptide Vogt, This hypothesis should be investigated in the context of nutrient abundance and stress over different developmental ages.

The mechanisms that regulate AKH secretion must be characterized in order to improve the utility of D. Its small size puts the fly model at a disadvantage to rodent models in some respects; for example, electrophysiological assays performed using dissected and cultured α and β cells are rarely used in fly research Fridell et al.

However, flies possess traits that present an advantage over rodent models, such as a short life cycle and ease of controlling genetic background. One of the great strengths of D. melanogaster research is the ever-expanding library of transgenic lines that permit spatiotemporal-specific manipulations of CC function and AKHR signaling pathways.

This section discusses bioassays that can be established—or adapted from existing protocols—to improve fly models of metabolic syndrome. Some exciting avenues for future AKH research are also highlighted.

First, a crucial weakness in D. melanogaster metabolic research must be addressed—the ability to quantify hemolymph sugar and AKH titers.

Dysregulation of blood glucose levels is diagnostic of pre-diabetic and diabetic states, and this phenotype is quantifiable in D. melanogaster metabolism research. Circulating AKH titers in D. melanogaster are estimated to be in the low femtomolar range and this makes the reliable quantification of AKH titers an ongoing challenge Isabel et al.

Unlike DILPs that are large enough to be tagged for quantification of secretion, the AKH octomer is too small for this technique Park et al. This problem was circumvented by quantifying phenotypes that are predicted to indicate changes in AKH secretion. These surrogate methods include altered lifespan during starvation Braco et al.

The precise quantification of circulating sugar i. Existing assays are efficient and highly replicable, and use enzymatic reactions that permit colorimetric sample quantification Buch et al. The ideal protocol will also allow for quantification of lipid and hormone e.

High performance liquid chromatography HPLC has been used to quantify glandular and hemolymph ecdysteroid titers Yamanaka et al.

Mass spectrometry MS methods benefit from high sensitivity and requirement for low sample volumes and can be used in conjunction with isotope labeled nutrients and hormones.

Combined HPLC and MS techniques were used to quantify tissue specific lipid accumulation Tuthill et al. AKH titers can be quantified by spiking samples with a known quantity of isotope-labeled AKH e. Another MS technique, tandem mass tagging TMT of proteins and nucleic acids, permits sample multiplexing.

In adults, the relatively small hemolymph volume and sclerotized cuticle makes sample collection more challenging than in larvae. Hemolymph can be extracted from adults by poking holes in the cuticle or removing the head and spinning the flies in a centrifuge Tennessen et al.

An alternative method that does not require anesthesia involves placing an adult inside a trimmed pipette tip, amputating one antenna, and apply low air pressure to the body to exude a droplet of hemolymph MacMillan and Hughson, Another essential development for D.

melanogaster metabolic syndrome research is a clinically relevant measure of obesity. The body mass index BMI standardizes body mass to body size using height as a surrogate measure of size and is used to diagnose overweight and obese humans Gutin, Obesity in flies is typically reported as whole body lipid content standardized to whole body protein content under the assumption that protein content is always constant across treatments and is directly proportional to body size.

Whole body macronutrient quantification is superior to the use of body mass in obesity research because the distinction between lipid and non-lipid molecules cannot be made. However, the assumption that whole body protein content is always constant and proportional to body size is rarely tested.

This bears great impact on fly metabolic research because transgenic and nutritional treatments that challenge energy homeostasis will stimulate protein catabolism for energy production as starvation progresses. When whole body protein content is altered by experimental conditions it is clearly an inappropriate surrogate measure for body size in obesity research.

Furthermore, it cannot be used as a constant against which lipid content is standardized for comparison between treatment groups.

Alternatives to this method are to use wing surface area or thorax length as a measure for adult body size Delcour and Lints, ; McBrayer et al. It needs to be noted that wing surface area is sometimes inconsistent with body size. Wing measurements may be less appropriate than thorax length, particularly where wing imaginal disk growth—mediated by DILP2 and DILP8—may be affected differentially between experimental and control lines Brogiolo et al.

Variation in genetic background can influence development and body size. The contribution of genetic background to this and other traits can be controlled through the backcrossing of mutant lines into an isogenic background Greenspan, For life stage-specific experiments, GeneSwitch GS provides temporal control over transgene expression via drug RU, mifepristone -dependent activation of GAL4 activity Osterwalder et al.

This controls for the effects of genetic background mutations on development in transgenic experiments, and recent advances have helped to reduce RU side effects Robles-Murguia et al.

In adult life stage-specific research, GS-GAL4 prevents developmental effects of GAL4-UAS activity in the experimental F1 line that cannot be controlled for in the GAL4 and UAS control lines e. The use of other GAL4 regulators e. This kind of error is misleading and creates flawed hypotheses of obesity mechanisms.

The international D. melanogaster community collaborates to study metabolic syndrome by sharing reagents and expertise. The utility and replicability of this research depends upon rearing flies in a consistent nutritional environment. While this is easily accomplished within one lab, it is rare that multiple lab groups use the same nutrient medium.

Given the significant influence of nutritional history on fly development and metabolic health, the establishment of a standardized nutrient medium will aid international collaborative efforts by removing the uncertainty associated with nutrient experience when comparing experimental results between groups.

The recipe for a standardized diet was developed to meet this need in the D. melanogaster research community Piper et al. This holidic diet is a precise blend of chemically defined ingredients that are available from chemical supply companies. The purity of these ingredients makes it possible for different labs to follow the same recipe and create identical nutrient media.

Another benefit of using this diet is that precise nutritional manipulations are easily designed and replicated. There are also concerns regarding the viability of some fly lines—particularly sensitive ones—on this nutrient medium.

Researchers take great care to control the genetic background of their fly stocks to prevent confounding effects of genetic variation on their phenotypes of interest.

The control of nutrient background is far simpler and prevents confounding effects of variation in nutritional history. Future efforts that modify the holidic diet—or develop new diets—provide the means to control this variable by standardizing the use of one standard nutrient medium in Drosophila research labs.

Drosophila has not lived up to its potential as a model organism for metabolic research Owusu-Ansah and Perrimon, As was made clear in this review, knowledge of regulatory mechanisms governing AKH secretion lags behind that of glucagon secretion in mammals.

This is one of the most important advances in AKH research that must be made to improve the utility of fly metabolism research in clinical research. Knowledge gaps in any of these four mechanisms governing glucagon and insulin physiology will severely limit the development of diabetes models.

This review identified promising areas for investigations into intrinsic mechanisms of AKH physiology that will contribute to models for the pre-diabetic and diabetic states of hyperglucagonemia and hyperglycemia.

Circadian regulation of behavior and physiology provides essential input to homeostatic control of metabolism. Energy expenditure changes between sleep and wake cycles and this requires changes in AKH and DILP secretion.

The PDF is a neuropeptide that is required for maintaining circadian rhythms and activity Renn et al. Its receptor, PDFR, was identified in the CC where its activity decreased starvation resistance and increased locomotion in fed flies Braco et al.

A possible explanation for these results is that PDF signaling in the CC promoted AKH secretion. The presence of PDFR in the CC identifies PDF signaling as a putative extrinsic factor that regulates AKH physiology.

cAMP promotes voltage gated ion channel conductance in excitable cells and is known to directly phosphorylate cardiac L-type VGCCs Siggins, ; Gao et al. It is possible that PDF acts in the CC to modulate cell membrane excitability by promoting cAMP phosphorylation of a VGCC subunit Perry et al.

In this putative role, PDF confers the regulatory influence of circadian rhythmicity upon AKH secretion. An exciting area for future research lies in characterizing the functional parallels between the AKH and GnRH orthologs.

Activation of the HPG axis through GnRH signaling at the onset of puberty stimulates the transition from juvenile to adult life in mammals Parent et al. Juvenile metabolic stress caused by famine or low socioeconomic status perturbs HPG activity and thereby contributes to the pathogenesis of metabolic syndrome both within and across generations Habtu et al.

Adipokinetic hormone altered the timing of larval development in responsive to low nutrient stress, and AKHR was implicated in the intergenerational transmission of the effect of nutrient stress on lipid homeostasis Palu et al.

AKHR signaling in the fat body activated the PKA-LKB1-SIK3-HDAC4 pathway Choi et al. Chronically elevated glucagon signaling suppressed SIK3 via the PKA-LKB1 pathway and caused HDAC4-mediated activation of FOXO to produce a pre-diabetic hyperglycemic state Luong et al.

This concurs with a recent report that AKHR signaling in the fat body mediated the hyperglycemic response to a high sugar diet Song et al. Epigenetic mechanisms play a causal role in the inheritance of acquired metabolic traits Somer and Thummel, As an epigenetic modifier, the histone deacetylating activity of HDAC4 is a candidate mediator of intergenerational transmission of nutrient stress effects via epigenetic inheritance.

The epigenetic effects of HDAC4 are particularly relevant due to its effect on the expression of genes that regulate the glycemic index Kasinska et al.

The dual functionality of AKH as a glucagon-like and a GnRH-like peptide presents great potential for understanding the etiological basis of metabolic syndrome, as well as the means whereby the effects of nutrient stress are transmitted across generations through altered HPG axis activity.

BNH confirms being the sole contributor of this work and has approved it for publication. BNH was supported by a Natural Sciences and Engineering Research Council of Canada and Canadian Institute for Advanced Research grant to Marla B. The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers.

Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. BNH wishes to thank the reviewers for improving this manuscript through their insightful and constructive input.

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It is produced by the alpha cells , found in the islets of Langerhans , in the pancreas , from where it is released into the bloodstream. The glucagon-secreting alpha cells surround the insulin -secreting beta cells , which reflects the close relationship between the two hormones.

To do this, it acts on the liver in several ways:. Glucagon also acts on adipose tissue to stimulate the breakdown of fat stores into the bloodstream. Glucagon works along with the hormone insulin to control blood sugar levels and keep them within set levels. Glucagon is released to stop blood sugar levels dropping too low hypoglycaemia , while insulin is released to stop blood sugar levels rising too high hyperglycaemia.

It works in totally opposite way to insulin. The release of glucagon is stimulated by low blood glucose, protein -rich meals and adrenaline another important hormone for combating low glucose. The release of glucagon is prevented by raised blood glucose and carbohydrate in meals, detected by cells in the pancreas.

For example, it encourages the use of stored fat for energy in order to preserve the limited supply of glucose. A rare tumour of the pancreas called a glucagonoma can secrete excessive quantities of glucagon.

This can cause diabetes mellitus, weight loss, venous thrombosis and a characteristic skin rash. Unusual cases of deficiency of glucagon secretion have been reported in babies.

This results in severely low blood glucose which cannot be controlled without administering glucagon. Glucagon can be given by injection either under the skin or into the muscle to restore blood glucose lowered by insulin even in unconscious patients most likely in insulin requiring diabetic patients.

It can increase glucose release from glycogen stores. Also, he says when there's ATP it prevents potassium from leaving the cell so the cell membrane becomes depolarized. How can it be depolarized if the cell is more positively charged than the outside to begin with, and it gets even more positively charged when there's ATP?

Under the resting condition, the potassium ions leave the cell through "leaky" open protein channels and will continue doing so as long as their concentration in the cell is higher than their concentration outside of the cell.

This means that when potassium ions leave the cell, their concentration outside is less than inside of the cell. Therefore, the correction to the video is accurate.

As under the resting conditions there is a negative resting membrane potential around negative 50 to 70 mV , this leads to the cell membrane depolarization making it less negative.

the video shows where the glucose is going into the cell glut after some steps the calcium help the insulin to leave the cell right? i thought the glucose cant get into the cell with out insulin. can you help me with this question please. Direct link to enxhi.

How can the beta cells be polarized by facilitated diffusion? What drives the movement of potassium from inside the cell to outside the cell if it is going against it's concentration gradient? Kiran Virani. How would the pancreas and liver respond to hypoglycaemia?

Candace Lei. Hypoglycemia means your blood glucose level is way too lower than the normal level. In that case, the pancreas will secrete glucagon and signal the liver to carry out glycogenolysis breakdown of glycogen to glucose in order to raise the blood sugar level.

Noted gluconeogenesis is also promoted by increase level of glucagon, yet the liver will not go to that way unless your body is at a fasting state. Tommy Tang. Is there any more detail on how alpha cells release glucagon? Or do we only have discovered amino acids trigger glucagon release?

Cody Weiler. why do they say in their edit that potassium is higher inside the cell compared to outside. Isn't potassium always leaving at rest making it higher outside compared to inside? Video transcript - [Voiceover] As you can see on this gentleman right here, he's got a liver, and then this organ down here is referred to as the pancreas.

Now the pancreas sits in the retroperitoneum which relative to the liver, which sits in the peritoneum, or in the abdomen, the pancreas is found to the back and to the left, to the back and to the left. And what's distinctive about the pancreas is it's blood supply. And so we can go through that in a little more detail after I blow up the pancreas right here and move it over just a little bit.

Now the pancreas is like most organs, in that it receives oxygen rich arterial blood flow and gives off oxygen poor blood flow through the venous system. So this is the venous blood right here. And this is the arterial blood. But in addition to these two things, the pancreas also receives blood flow from the intestine, which I can draw right here.

The small intestine will deliver unique nutrient rich blood through the pancreas and this is nutrient rich blood through the portal venous system. This is the portal venous blood flow. And once this nutrient rich blood flows through the pancreas it will trigger hormone release.

Hormones such as insulin and glucagon and that'll actually be released into the portal venous blood and travel along with the rest of the nutrients to the liver. And the cool thing about the hormones going straight to the liver first means that the effects they have there are four times greater than what you will see in the rest of the body.

So insulin and glucagon from the pancreas will have four times greater effect in the liver than in the rest of the body. But now the thing about the pancreas is that it doesn't just contain insulin and glucagon hanging out in random cells, they're organized. So if we blow up a small part of the pancreas right over here, we would see this.

Which is a collection of cells here, like an island, surrounded by other cells. These other cells on the outside secrete enzymes that go into the GI tract, and we won't worry too much about them now, but the cells here in this island are referred to as the islet of langerhans.

So it's the islet of langerhans. Which is just a fancy term for an island of cells. And the way the cells are organized in here is very structured. You'll have what are called beta cells in the middle of the island and on the outside you'll have what are called alpha cells. So alpha cells on the outside.

And the key thing to remember here is that your beta cells release insulin while the alpha cells release glucagon.

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Lefebvre PJ Early milestones in glucagon research. Diabetes Obes Metab 13 Suppl 1 :1—4. You'll have what are called beta cells in the middle of the island and on the outside you'll have what are called alpha cells.

So alpha cells on the outside. And the key thing to remember here is that your beta cells release insulin while the alpha cells release glucagon. The alpha cells release glucagon.

And we can actually go into further detail about how beta cells, for instance, secrete insulin into the blood. Let's start by focusing on this beta cell right here. I'll be sure to label this.

This is a beta cell right here. This is our beta cell and these guys store insulin. So I'll write insulin here in this secretory vesicle.

And I'll show you how it's released into the blood stream. This secretory vesicle, much like many secretory vesicles in the body, will release their contents outside of the cell if there's calcium present.

So I'll put this calcium receptor here for now. The other thing that's unique about beta cells is that they have these potassium channels. So potassium channels that allow potassium to leave beta cells through facilitated diffusion.

So they're just naturally leaving the beta cell over time. Which means that at rest there's a lot more potassium ions living outside of the beta cell than there are inside of the beta cell. And that's an important distinction because that's how we prevent the beta cell from being depolarized or getting a more positive charge within the cell.

And this potassium channel also has a receptor on it, that I promise I'll go into more detail about in a minute. But it grabs onto ATP, the basic molecule of energy.

And in addition to the potassium channel, there's also this calcium channel. So it's a calcium channel that's sitting here like in most cells and open through depolarization. And we'll go into how that happens in a second. All right, so now we're ready.

How does insulin leave the beta cell? Well the first thing that has to happen is that glucose needs to enter the cell somehow, because when there's a lot of glucose around we wanna store it away. That's what insulin's supposed to do. And the way it enters is through this unique transporter.

It's called the glut 2 transporter. And it allow glucose to enter into your beta cell. Once we get glucose inside of the cell, glucose will undergo what it usually does in most cells, processes such as glycolysis or be broken down into things that are sent through the krebs cycle.

And doing this second thing here will produce a lot of ATP molecules. We mentioned ATP already. ATP is that basic form of energy. And it's important in this cell, because once we start to build up the amount of ATP that's present, some of it will go down here to this potassium channel and bind the ATP receptor that sits here.

Now the interesting thing about this ATP receptor is that once it locks in, it'll actually block off this channel. It'll prevent potassium from leaving, so the next thing that'll happen is that the amount of potassium in the cell will start to skyrocket because there's no way for it to get out anymore.

So you'll have a lot more potassium, or a lot more positive charge inside of the cell, than you have relative to what's outside. And what that's going to do is cause depolarization, depolarization of the membrane of the beta cell.

That then will go and activate these voltage gated calcium channels, allowing calcium to enter the beta cell, which in turn can also cause calcium dependent calcium release into the cell. But overall it starts increasing the amount of calcium that's present on the inside.

And as you might remember, the insulin secretory vesicle has a calcium receptor here. So sure enough, the next thing that occurs is that calcium will bind this receptor, causing this vesicle to fuse with the membrane of the beta cell.

That'll cause insulin to be kicked out of the beta cell and be released into the blood stream. This step here, as you might recall, this final step that kicks the insulin out of the cell, is what's called exocytosis. Exocytosis, where a vesicle fuses with the cell membrane to release it's contents into the outside, or the extracellular space.

Which in this case, is the portal venous blood, which will send it to the liver. So that's how insulin is released from beta cells. What about glucagon? How is it released from alpha cells? Trehalose is a non-reducing disaccharide that functions as a store of glucose whose levels fluctuate broadly in the hemolymph Chown and Nicholson, This coordination is achieved through cell autonomous nutrient-sensing of circulating glucose titers Kim and Rulifson, ; Rorsman et al.

The mammalian pancreatic α and β cells are cell-autonomous nutrient sensors that monitor blood glucose homeostasis. The response to changes in blood glucose homeostasis must be rapid and efficient.

Chronically reduced glucose hypoglycemia decreases energy production in metabolizing tissues and can cause death, and chronically increased glucose hyperglycemia produces reactive oxygen species that cause cytokine storm-induced apoptosis Verzola et al.

α cells secrete glucagon in response to hypoglycemia and β cells secrete insulin in response to hyperglycemia Rorsman et al. Fruit flies similarly use a glucagon-like peptide called the adipokinetic hormone AKH and eight Drosophila insulin-like peptides DILP1—8 to regulate hemolymph insect blood glucose levels Ikeya et al.

Due to their α and β cell-like functions, the CC and IPCs are together viewed functionally as the fly pancreas. The CC is also known as the AKH producing cells APCs —this review will use the original CC nomenclature in referring to this tissue.

This relationship is more complex in Drosophila , where AKH and all eight DILPs do not always act in an antagonistic manner, nor do all DILPs regulate haemolymph glucose titers; this will be expanded upon below. Another important distinction between mammals and Drosophila is that—unlike glucagon—AKH does not catabolize glycogen, which is stored along with lipids in the fat body Grönke et al.

In flies, the target of brain insulin tobi is thought to convert glycogen stores to glucose; interestingly, tobi is regulated systemically by both AKH and DILP perhaps DILP3 in response to protein and sugar intake, and ablation of either the IPCs or CC eliminates tobi expression and promotes glycogen accumulation Buch et al.

Growing insight into the contribution of glucagon to the pathogenesis of diabetes as well as further characterization of regulatory mechanisms for glucagon secretion invigorated this field of research Leiss et al.

These developments make a review of this research timely. An authoritative review of the catabolic action of AKH on the insect fat body is published elsewhere Heier and Kühnlein, This review focuses primarily on the regulation of AKH activity through its biosynthesis and secretion from the CC, and covers seminal research performed using rodents.

Current understanding—gleaned from murine and fly research—of the mechanism whereby CC cell autonomous nutrient sensing is mediated by ATP-sensitive potassium K ATP channels is reviewed in detail.

The role that this mechanism plays in regulating insulin secretion must also be discussed, as the physiology of glucagon and insulin cannot be thoroughly investigated independently of one another Unger and Orci, This review closes with a discussion of the application of CC and AKH research to the development of fly models for metabolic syndrome.

Strengths and weaknesses of existing fly models are addressed. At 25°C and in a nutrient abundant environment, embryogenesis in D. melanogaster requires 24 h and is followed—over 4 days—by three larval instars, wandering behavior, and pupariation. The larval body plan is reorganized during pupal metamorphosis and the sexually mature adult ecloses from its puparium 5 days after pupariation Ashburner, The CC is a bilobed neuroendocrine tissue that develops from a pair of neuroblasts in the stage 10 embryo.

It is unclear whether these cells originate from head mesoderm or from anterior neuroectoderm de Valesco et al. The neural stem cell progenitors of the CC were reported to originate from the anterior neuroectoderm because these cells expressed genes that are orthologous to those expressed in progenitors of the mammalian anterior pituitary gland Wang et al.

This suggests common evolutionary origins of neuroendocrine control of metabolism. During larval life, the CC—along with the prothoracic gland PG and corpus allatum CA —forms part of the ring gland and is comprised of approximately seven cells per lobe in third instar larvae Lee and Park, During pupal metamorphosis, the CC cells are conserved and migrate posteriorly to the brain lobes to sit on the dorsal surface of the foregut and anterior to the cardia.

The adult CC cells are positioned around the heart and the CA sits on the dorsal surface of the CC; the PG is lost during metamorphosis.

The distinction between lobes in the adult CC is not readily discernible, and the adult CC was reported to consist of 11—16 cells Lee and Park, Neural projections from the CC extend to the heart, esophagus and central nervous system in adults and larvae, as well as the larval PG and the adult crop Kim and Rulifson, ; Lee and Park, Recent work has identified the IPCs as targets of CC axonal projections to the larval CNS where they regulate the sugar-dependent secretion of DILP3 Kim and Neufeld, The IPCs also target the CC and DILP2—whose secretion is stimulated by amino acids—was identified in a subset of CC cells Rulifson et al.

CC axonal projections to the heart transport endocrine peptides to the hemolymph for dispersal throughout the body. AKH secreted from these neurons also stimulates heart contractions to improve dispersal to target tissues Noyes et al.

IPC neural projections also extend to the heart where they have extensive contact with CC axons Kim and Rulifson, The function—if any—of these connections is unknown. A single pair of neurons extends from the adult CC to the crop and has been hypothesized to regulate crop emptying in D.

melanogaster Lee and Park, The crop is the primary storage organ for carbohydrates in flies, as muscle and fat body glycogen stores are very small Chown and Nicholson, The regulation of crop emptying is crucial to the early response to starvation.

In the blowfly, Phormia regina , these neurons extend down the crop duct where they project onto the supercontractile muscles sheathing the crop Stoffolano et al. AKH is transported to these muscles and stimulates muscle contraction and crop emptying. Corpora cardiaca axons containing AKH project to the PG: this was reported in D.

melanogaster , but their function is unknown Kim and Rulifson, The PG is the site of biosynthesis and secretion of ecdysteroids and plays a crucial role in regulating the timing of developmental transitions during larval life Yamanaka et al.

This CC neuroanatomy prompted the hypothesis that the CC and AKH may influence development through the regulation of ecdysteroid physiology.

However, CC ablation, AKH receptor AKHR mutant, and AKH mutant experiments did not identify a developmental role for the CC or AKH Kim and Rulifson, ; Lee and Park, ; Grönke et al. Recent work identified a nutrient-dependent role for AKH in larval development, as well as its influence on the PG; this is discussed further below Hughson et al.

The D. melanogaster akh gene also: dAkh ; hereafter referred to as akh was sequenced and localized between 64A10 and 64B1, 2 on chromosome 3L Noyes et al. Consisting of 2 exons, the first of which encodes the signal sequence and first amino acid residue pGlu, pyroglutamic acid , akh encodes a polyadenylated mRNA approximately bases in length.

Noyes et al. melanogaster display high conservation in structure with the AKH of other insect species, the intron-exon sequences and C terminal peptide sequences do not show this same high degree of conservation. akh mRNA expression was localized exclusively to the larval and adult CC and all or nearly all CC cells express akh Noyes et al.

melanogaster AKH peptide DAKH hereafter referred to as AKH is biosynthesized in and secreted from the CC cells. AKH is synthesized as a pre-prohormone that is processed to its bioactive form by the pre-prohormone convertase amontillado amon Rhea et al.

The DAKH is an octomer pGlu-Leu-Thr-Phe-Ser-Pro-Asp-Trp-NH 2 Schaffer et al. The identification of AKH peptides in other insect species revealed that although conservation of gene and peptide structure was evident, variation in amino acid sequence at the seventh position imparts significant consequences for AKH bioactivity.

The seventh amino acid is aspartic acid in D. melanogaster and is asparagine in other insects Schaffer et al. In vivo assays reported a fold reduction in the activity of D. melanogaster AKH in the grasshopper Schistocerca nitans whose AKH bears asparagine at this seventh position.

Aspartic acid is thought to impart a charge on AKH at physiological pH that is absent in AKH bearing asparagine. The charged D. melanogaster AKH is hypothesized to produce a poor interaction with receptors for uncharged AKH peptides.

The AKHR will be discussed below. As with Akh mRNA expression, AKH-immunoreactivity IR patterns were restricted to the CC in whole mount immunohistochemical analyses of third instar larval and adult tissues using antibodies against AKH Kim and Rulifson, ; Lee and Park, ; Isabel et al.

Whole body AKH levels in adult flies are not strain dependent i. Oregon R , but AKH peptide content in 7—9 d. However, within sexes, no correlation exists between adult body weight and whole body AKH peptide content Noyes et al. The biosynthesis of endocrine compounds is not necessarily coupled with secretion Harthoorn et al.

This is evident in AKH physiology where akh transcriptional activity and pre-prohormone processing are not affected by secretory stimuli Harthoorn et al. Further evidence that AKH biosynthesis is tightly regulated comes from the observation that flies with 1 or 3 copies of akh all contain similar levels of AKH Noyes et al.

APRP is functionally orphan and does not affect carbohydrate or lipid metabolism in Locusta migratoria and the grasshopper Romalea microptera Oudejans et al. APRP belongs to the growth hormone-releasing factor GRF superfamily, which includes glucagon, glucagon-like peptides 1 and 2, and the GRF peptide itself.

APRP shares the greatest peptide sequence homology with the mammalian GRF De Loof and Schoofs, ; Clynen et al. GRF influences developmental progression in mammals, and this prompted the hypothesis that APRP is functionally homologous to GRF—that is, APRP is a putative developmental regulator.

However, APRP was demonstrated to have neither ecdysiotropic effects in L. migratoria , nor to influence the ecdysteroid-dependent timing of developmental transitions in D.

melanogaster De Loof et al. The CC receives both extrinsic and intrinsic regulatory inputs. An AKH-mediated autocrine feedback loop negatively regulates akh expression Gàlikovà et al. Nutrition directly influences CC glucose metabolism in a manner that regulates cell membrane electrical activity; this is discussed thoroughly in the next section of this review.

Other nutrient-derived factors include: the muscle-derived cytokine unpaired-2 Upd2 that alters AKH secretion Zhao and Karpac, ; α-bursicon is secreted from enteroendocrine cells and signals through Dlgr2 to negatively regulate AKH production and systemic signaling Scopelitti et al.

Additionally, the gustatory water-sensing ion channel pickpocket28 ppk28 negatively regulates AKH secretion Waterson et al. These and other factors that provide regulatory input to the CC are reviewed elsewhere Nässel and Winther, ; Ahmad et al. The physiological effects of AKH are mediated by the D.

melanogaster AKH receptor DAKHR; also AKHR. melanogaster AkhR is the first insect AkhR gene reported to encode a seven-transmembrane domain G-protein coupled receptor, or GPCR Staubli et al.

AKHR is structurally- and evolutionarily-related to the mammalian gonadotropin-releasing hormone GnRH receptor, and was named originally named GnRHR Staubli et al. When the ligand of the D. melanogaster GnRHR was identified as AKH, this receptor was renamed AKHR Staubli et al.

AKHR will be discussed further below. In situ localization of AkhR expression and AKHR protein abundance within the fly is complicated by the difficulty in distinguishing between highly conserved regions of GPCRs. Reporter gene expression driven by AkhR -GAL4 in adults suggests that AkhR is expressed in the fat body tissues of the head and abdomen Bharucha et al.

AkhR -GAL4 also drives expression in the sweet sensing gustatory receptor neurons of the suboesophageal ganglion SOG Bharucha et al. These AkhR -GAL4-driven expression patterns are not comprehensive. Tissue-specific expression of AkhR -RNAi also identified roles for AKHR signaling in the IPCs, the PG, and in four interoceptive SOG neurons ISNs Kim and Neufeld, ; Jourjine et al.

Eight DILPs are produced in Drosophila and their expression patterns and functions vary according to discrete stages of life; this information is thoroughly reviewed elsewhere Owusu-Ansah and Perrimon, ; Nässel and Vanden Broeck, The regulation of DILP biosynthesis, secretion, and signaling in Drosophila is very complex, and only a brief summary can be provided here.

Insulin signaling in Drosophila is more complex than in mammals, and it is inappropriate to generalize all DILPs as being direct actors in metabolic homeostasis in the same sense that β cell-derived insulin is in mammals.

It is similarly inappropriate to oversimplify the activities of AKH and all DILPs as being antagonistic. However, specific DILPs do directly alter haemolymph glucose titers e.

Adipokinetic hormone and DILP secretion must be coordinated so that their antagonistic actions preserve hemolymph glucose homeostasis. Central to this goal is the ability of the CC and IPCs to monitor energy homeostasis through cell autonomous nutrient sensing of circulating glucose titers.

This is accomplished by the evolutionarily conserved K ATP channels. ATP-Sensitive Potassium channels function as cell autonomous nutrient sensors in mammalian pancreatic α and β cells for comprehensive reviews, see: Ashcroft and Rorsman, ; Rorsman et al.

melanogaster larval and adult CC; these channels are also present in the adult—but not larval—IPCs Kim and Rulifson, ; Fridell et al. K ATP channels also contribute to healthy mammalian and Drosophila cardiac function Akasaka et al.

The K ATP channel contains two subunits comprised of four regulatory sulfonylurea receptors SURx: SUR1 in mammals; Sur in flies and four pore-forming weakly inward rectifying potassium channels Kir6. x: Kir6.

x bears an ATP-binding domain and SURx bears a Mg-ADP-binding domain: Kir6. x-ATP binding stimulates channel closure and cell membrane depolarization; SURx-Mg-ADP stimulates channel opening and cell membrane polarization.

The weakly inward rectifying action of the Kir6. Glucose transporters bring glucose into the mouse α GLUT1 and GLUT4 and β GLUT2 cells where it enters the Krebs cycle for ATP production Heimberg et al.

This stimulates cell membrane depolarization and—along with an unidentified depolarizing current—causes action potential firing that regulates insulin and glucagon secretion Rorsman et al. Paradoxically, K ATP channel closure causes depolarization and action potential firing in both cell types but promotes insulin secretion from β cells while inhibiting glucagon secretion from α cells.

The means whereby α and β cell K ATP channels produce opposite effects on secretion in response to the same glucose titers is still incompletely understood. Recent work demonstrated that this is likely due to differential glucose sensitivity of K ATP channels between the two cell types, which significantly alters cellular excitability and action potential firing Göpel et al.

I will review electrical regulation of both α and β cells in order to contrast important differences in effect of K ATP channel activity between the two cell types. Insulin secretion from β cells is stimulated by cell membrane depolarization caused by K ATP channel closure Cook and Hales, ; Rorsman et al.

β cell K ATP channel conductance is high i. Electrical regulation of insulin secretion from β cells is thoroughly reviewed elsewhere Sarmiento et al.

α cells are more sensitive to glucose than are β cells. In contrast to β cells, α cells show very low K ATP channel conductance at 1 mM of glucose; this results from α cell K ATP channels having a 5-fold greater sensitivity to ATP produced by glucose phosphorylation Zhang et al. As a result, small changes in K ATP channel activity i.

The high sensitivity of these K ATP channels is crucial as it makes α cells electrically active at low glucose concentrations, thus stimulating VGCC activity and permitting glucagon secretion at glucose concentrations that inhibit insulin secretion from β cells.

The crucial role played by voltage-gated sodium channels VGSCs in mediating this process in α cells that is described below. Just as importantly—because glucagon must be secreted only during hypoglycemia—increasing glucose concentrations to 6 mM rapidly closes all remaining α cell K ATP channels.

This produces strong membrane depolarization and action potential firing, and—through the activity of VGSCs—prevents glucagon secretion during hyperglycemia. Glucagon secretion is thus both stimulated and inhibited by varying magnitudes of K ATP channel activation.

This relation between K ATP channel conductance and glucagon secretion follows an inverted U-shaped dose response curve where maximum secretion occurs at 1 mM glucose, and small increases or decreases in conductance inhibit secretion Zhang et al.

α cell membranes bear VGSCs that are activated by K ATP channel closure and membrane depolarization at 1 mM glucose. The VGSCs produce rapid and short-lived amplification of the moderate depolarizing stimulus that is produced by K ATP channel closure at low glucose concentrations.

When all α cell K ATP channels close in response to hyperglycemia, further membrane depolarization increases action potential firing and inactivates VGSCs. VGSC closure reduces action potential firing and spike height, VGCCs are subsequently inactivated, and glucagon secretion is inhibited.

The precise regulation of ion channel activity through K ATP channel-mediated nutrient sensing underlies the proper timing of glucagon and insulin secretion.

Homeostatic control of blood glucose homeostasis is highly sensitive to any factors that dysregulate channel function.

Mutations in K ATP channels, VGCCs, and VGSCs that perturb their function are currently the focus of research aimed at identifying causal mechanisms that underlie the pathogenesis of diabetes. The precise mechanism whereby α cell membrane electrical activity and glucagon secretion are regulated remains to be elucidated.

Although glucose-dependent K ATP channel activity certainly plays a prominent role in regulating the inverted U-shaped curve of α cell membrane electrical activity described above, it is not the sole determinant of glucagon secretion.

Evidence suggests that K ATP channel-independent mechanisms can contribute to this pattern of electrical activity and produce glucagonostatic effects at high glucose concentrations through both extrinsic paracrine and intrinsic means. In β cells, insulin secretion is inhibited by AMPK and stimulated by PKG Granot et al.

This is mediated by mechanisms that are both dependent and independent of AMPK. Liver kinase B1 LKB1 induces AMPK activity to inhibit insulin biosynthesis and secretion in both a glucose- and amino acid-responsive manner da Silva Xavier et al.

AMPK also inhibits insulin secretion via a leptin-mediated feedback loop Tsubai et al. In response to feeding, insulin promotes leptin secretion from adipose tissue, and leptin signaling in β cells subsequently induces protein kinase A PKA activation of AMPK Park et al.

Leptin-PKA-AMPK signaling regulates membrane polarity—and thus cell excitability—by promoting K ATP channel trafficking to the β cell membrane Cochrane et al. This increases K ATP channel conductance and hyperpolarizes the cell membrane.

Importantly, this occurs only in a progressively fasted state when the glucose:leptin titer ratio decreases to a level where continued insulin secretion would produce a hypoglycemic state Park et al.

In β cells, PKG promotes insulin secretion in a fed state either by phosphorylating and closing K ATP channels or by phosphorylation of proteins that indirectly target K ATP channels Soria et al. PKG activity is induced by atrial natriuretic peptide ANP signaling in β cells Undank et al.

PKA also phosphorylates and closes K ATP channels, and PKG promotes this inhibitory effect by preventing phosphodiesterase deactivation of PKA Undank et al.

This PKA-mediated increase in insulin secretion appears contradictory to its inhibitory effect reported above; however, PKA inhibition of K ATP channels is mediated by PKG signaling, whereas leptin-PKA-AMPK signaling increases K ATP channel conductance in the absence of PKG activity Undank et al.

The complexity of the glucose-responsive and self-regulatory pathways present in β cells reflects the need for rapid responses in insulin secretion to changes in blood glucose levels.

This promotes glucagon secretion through an incompletely characterized signaling cascade Leclerc et al. Induction of AMPK by AMP is mediated by LKB1 during hypoglycemia, but AMPK is not the sole target of LKB1 phosphorylation in glucagon regulation Sun et al. This physiological effect suggests that—as in β cells—PKG might phosphorylate VGCCs and close these channels.

Further insight is provided by research into cardiac myocytes where nitric oxide stimulated PKG activity inhibits Ca v 1. The murine research reviewed above informs future research into the regulatory mechanisms of AKH secretion in D.

Endocrine research requires the ability to quantify changes in hormone secretion. However, circulating AKH titers in D. melanogaster are estimated to be in the low femtomolar range, and this makes the reliable quantification of AKH titers an ongoing challenge that will be addressed below Isabel et al.

Pharmacological and transgenic manipulations were used to implicate K ATP channels in the regulation of AKH secretion from the larval CC Kim and Rulifson, Tolbutamide is a diabetic drug that targets the Sur subunits of K ATP channels.

Tolbutamide treatment was used in conjunction with transgenic manipulations where the CC was ablated to show that the increase in glucose titers was dependent upon the CC. The effect of tolbutamide was inhibited when CC membrane depolarization was transgenically inhibited.

These experiments provided strong evidence for the existence of K ATP channels in the CC and for their regulatory role in AKH secretion Kim and Rulifson, Adult IPCs bear K ATP channels, and in vivo electrophysiological measurements of these cells were used to discern the influence of K ATP channels on membrane potential; the potential for applying this technique to the CC has not been explored Fridell et al.

A major contribution to the characterization of mechanisms that regulate CC cell membrane potential and AKH secretion was recently reported Perry et al. Three genes that encode components of K ATP channels Sur , calcium channels Ca-Beta , and potassium channels sei were identified through RNAi-mediated knockdown as regulatory candidates for excitation-secretion coupling for AKH in the CC.

These results provided further support for the nutrient-sensing role of K ATP channels in the CC. The identification of CC ion channel components greatly improves the utility of D.

melanogaster as a model for α cell dysregulation, hyperglucagonemia, and the pathogenesis of T2DM. The murine cGKI research described above prompted the hypothesis that PKG—encoded by dg2 in D.

melanogaster —might negatively regulate AKH secretion. Reduced dg2 expression in the larval CC reduced intracellular AKH abundance, and this correlated with a low nutrient-dependent developmental delay and increased lethality prior to pupariation Hughson et al.

Compared to control genotypes, more of these larvae survived pupal metamorphosis and developed into adults with greater starvation resistance and increased body size to lipid content ratio, a trait associated with obesity in humans. This suggested that dg2 functioned in the CC to increase survival during larval development in a low nutrient environment, and but that this resulted in a tradeoff with starvation resistance during adult life Hughson et al.

Further research demonstrated that dg2 also influenced AKH abundance in the adult CC Hughson, in press. Reduced dg2 expression in the adult CC decreased intracellular AKH, but—in contrast to larvae—correlated with decreased body size to lipid content ratio. This effect correlated with evidence of increased systemic lipid catabolism and reduced starvation resistance during adult life.

As described above, the CC is developmentally orthologous to the mammalian anterior pituitary gland Wang et al. The PI location of IPCs of the fly protocerebrum is orthologous to the mammalian hypothalamus Wang et al.

Although there is little conservation between AKH and glucagon amino acid sequences, both hormones act through the same evolutionarily conserved signaling pathway to regulate transcriptional responses to hypoglycemia De Loof and Schoofs, ; Clynen et al.

The HP axis also regulates the time of onset of puberty. When the HP axis detects a minimum level of body growth during childhood it stimulates steroid hormone biosynthesis in the gonads Shalitin and Philip, The subsequent rise in steroid titers initiates the developmental transition from sexual immaturity to maturity.

Paracrine signaling between the hypothalamus and pituitary gland is mediated by GnRH, which stimulates the secretion of gonadotropins that enter circulation and stimulate steroid hormone biosynthesis and secretion from the gonads.

melanogaster , steroid hormones similarly regulate the timing of this developmental transition. The evolutionary relatedness of GnRHR and AKHR was introduced above. The conservation of AKHR and GnRHR prompted the hypotheses that AKHR influenced development by regulating ecydsteroidogenesis, and that AKH—in addition to its glucagon-like properties—possessed dual functionality as both a glucagon-like and GnRH-like peptide.

Conserved peptide sequences between AKH and GnRH seemed to provide support for this hypothesis Lindemans et al. However, recent work investigating AKH and AKHR loss of function mutant lines demonstrated that neither AKH nor AKHR affected developmental i.

While development was not altered in AKH loss of function mutants, recent work identified the possibility that AKH might play a role in ecdysteroid biosynthesis in the PG. Evidence comes from work demonstrating a role for AKH-regulated hormone sensitive lipase HSL activity in steryl ester metabolism and the intergenerational transfer of sterols Heier et al.

This pathway regulates catabolism of steryl ester lipid droplet stores and plays an essential role in ecdysteroid biosynthesis. While this work reported no effect of an HSL loss of function mutation on PG lipid droplets, these data came from animals reared in a lipid- and sterol-abundant feeding environment and larval development was not reported.

The possibility that this pathway influences ecdysteroid biosynthesis in sterol-limited or -deficient environments needs to be explored. This avenue of research is supported by a developmental role for AKH that was observed only in low nutrient conditions Hughson et al. Larvae reared in a low nutrient i.

This gene, dg2 , is orthologous to cGKI, which encodes the PKG that regulates alpha cell membrane excitability Leiss et al. This delay was AKH-dependent, and—as observed in AKH mutants reared in nutrient-abundant conditions—was absent in nutrient-abundant conditions Gàlikovà et al.

This trait was associated with GPCR-mediated active secretion of ecdysteroids from the PG as well as with AKH activation of the HSL pathway Yamanaka et al. It is vital to reemphasize that AKH mutants did not exhibit developmental defects, delays, or fitness consequences, and that this definitively demonstrated that AKH is not essential for development in a nutrient-abundant environment Gàlikovà et al.

There is no contradiction between this seminal work and the report of an AKH-dependent effect on developmental timing that was present only in low nutrient conditions Hughson et al. Instead, this identifies the possibility that in challenging nutritional environments AKH can play a non-essential role in development in a manner fitting for a stress peptide Vogt, This hypothesis should be investigated in the context of nutrient abundance and stress over different developmental ages.

The mechanisms that regulate AKH secretion must be characterized in order to improve the utility of D. Its small size puts the fly model at a disadvantage to rodent models in some respects; for example, electrophysiological assays performed using dissected and cultured α and β cells are rarely used in fly research Fridell et al.

However, flies possess traits that present an advantage over rodent models, such as a short life cycle and ease of controlling genetic background. One of the great strengths of D. melanogaster research is the ever-expanding library of transgenic lines that permit spatiotemporal-specific manipulations of CC function and AKHR signaling pathways.

This section discusses bioassays that can be established—or adapted from existing protocols—to improve fly models of metabolic syndrome. Some exciting avenues for future AKH research are also highlighted.

First, a crucial weakness in D. melanogaster metabolic research must be addressed—the ability to quantify hemolymph sugar and AKH titers. Dysregulation of blood glucose levels is diagnostic of pre-diabetic and diabetic states, and this phenotype is quantifiable in D.

melanogaster metabolism research. Circulating AKH titers in D. melanogaster are estimated to be in the low femtomolar range and this makes the reliable quantification of AKH titers an ongoing challenge Isabel et al.

Unlike DILPs that are large enough to be tagged for quantification of secretion, the AKH octomer is too small for this technique Park et al.

This problem was circumvented by quantifying phenotypes that are predicted to indicate changes in AKH secretion. These surrogate methods include altered lifespan during starvation Braco et al. The precise quantification of circulating sugar i.

Existing assays are efficient and highly replicable, and use enzymatic reactions that permit colorimetric sample quantification Buch et al. The ideal protocol will also allow for quantification of lipid and hormone e.

High performance liquid chromatography HPLC has been used to quantify glandular and hemolymph ecdysteroid titers Yamanaka et al. Mass spectrometry MS methods benefit from high sensitivity and requirement for low sample volumes and can be used in conjunction with isotope labeled nutrients and hormones.