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Acta , 22 Hess, B. Vinopal, R. O'Sullivan, W. Akkerman, J. Knowles, C. Amino acids being to break down and form this metabolite called oxaloacetate, and remember that oxaloacetate plays its unique role in its conversion of pyruvate back to glucose which occurs in gluconeogenesis.

Remember that it's kind of this intermediary. So pyruvate is converted to oxaloacetate and then essentially reenters the equilibria to form glucose. So you can imagine that if we have an influx of oxaloacetate, the equilibria will be pushed towards the opposite direction, that is, towards the production of glucose.

Now in addition, I wanna briefly mention another form of fast-acting regulation, which is call allosteric regulation. So what is allosteric regulation? Recall that all metabolic pathways have unique enzymes that catalyze or facilitate each step of the reactions along the metabolic pathways.

So you can imagine that if we have an enzyme here, I'm just drawing a simple structure, it has what's called an active site, where it actually binds the substrate of interest so it binds the, let's say, glucose molecule here, but in addition there are also molecules within a cell that we call allosteric regulators and these, by definition, bind to a portion of the enzyme that is not the active site.

So let's say we have an allosteric molecule that binds to a separate portion like right here. Now this allosteric molecule can have one of two effects. We say that allosteric molecules can be inhibitory, that is, by inhibiting enzymes, inhibit the pathway that utilizes those enzymes, or these allosteric interactions can be positive, that is, promote the action of enzymes and therefore promote the overall reaction in which those enzymes are involved.

So to put this in context with glycolysis and gluconeogenesis above, it turns out that ATP is actually a big allosteric regulator of one of these two pathways.

So recall that gluconeogenesis requires ATP, a net amount of ATP, to produce glucose. It's an anabolic building up pathway. On the other hand, in glycolysis, there is a net release of ATP and the oxidative breakdown of glucose.

And so we have a lot of ATP in a cell, think about, for a moment, which of these two pathways would be favored. Indeed, gluconeogenesis would probably be favored because it requires ATP. On the other hand, if there's a lot of ATP, that's kind of a sign to the cell to say, "Hey, we don't need to perform as much glycolysis "because we already have enough ATP available.

And specifically, it's a negative allosteric regulator, or an inhibitor, of these couple enzymes. Essentially it's putting the breaks on glycolysis and saying, "We have enough energy "and we don't need to produce any more.

So if the cell is running out of ATP, the cell probably won't want to be performing energy-requiring processes such as gluconeogenesis, and indeed, AMP is a negative allosteric regulator of one of the enzymes in gluconeogenesis. Alright, so that kind of finishes up our discussion of fast-acting forms of regulation.

So now let's talk briefly about slow-acting forms of regulation. So these types of regulation often take advantage of transcriptional changes within the cell.

So what do I mean by that? So let's first remind ourselves what transcription is. So remember that transcription is a process of taking DNA and making an mRNA transcript and then translating this in the cytosol of the cell to a protein product and when we're talking about proteins oftentimes we're talking about enzymes.

So I'm just gonna go write that here since it's relevant for our discussion. And so you can imagine for example that this might be very useful if the organism is in a longterm fasting state. It will want to essentially up-regulate the transcription of enzymes that promote something like gluconeogenesis so that it can dump glucose into the blood.

And notice here that even visually as it's implied here this process of going from DNA to mRNA to enzymes is going to take much longer than a simple Le Chatelier or allosteric regulation and so that's why this process is more of an adaptive process that allows the organism to adapt to more of long term changes that it experiences in its environment.

Now finally I want to add in one more form of regulation between fast- and slow-acting regulation which is called hormonal regulation.

So what is hormonal regulation? Well it's exactly what it sounds like. It's the ability for the body to essentially produce specific hormones which are simply molecules that travel in the blood to regulate whether glycolysis or gluconeogenesis is on or off.

And the two hormones that the body uses to regulate glycolysis and gluconeogenesis and pretty much, actually, all metabolic pathways, are insulin and another hormone called glucagon.

And depending on whether there is more insulin or more glucagon, the body will be more likely to do glycolysis or more likely to do gluconeogenesis. So let's talk about how that decision is made. Now hormones, like insulin and glucagon, are usually released by the body whenever the body deviates from a particular set point.

Now in the case of regulation of metabolism, the set point that we're interested in is the blood glucose level, and if we return back to our analogy here, this seesaw here, this pivot point we can think about as our set point. The blood glucose level: it's a specific amount of glucose that the body wants to have in the blood at all times.

Now to get more specific, if the blood glucose level rises it actually stimulates the body to release the hormone insulin, and if the blood glucose levels decrease, it stimulates the body to release the hormone glucagon. And so with that in mind, take a moment to think about which hormone, insulin or glucagon, promotes glycolysis, and which of these two hormones promotes gluconeogenesis.

Basically this is actually a macro-application of Le Chatelier's Prinicple, right? If we have too much blood glucose level, we want to get rid of it. How do we get rid of it? We break it down. And so indeed, insulin promotes glycolysis. On the other hand, when blood glucose levels are low, we want to return the equilibrium to normal, we want to pump more glucose back into the blood and we know that gluconeogenesis can accomplish that for us.

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Newer formulations of insulin and insulin secretagogues, such as sulfonylureas and meglitinides, have facilitated improvements in glycemic control.

While sulfonylureas and meglitinides have been used to directly stimulate pancreatic β-cells to secrete insulin,insulin replacement still has been the cornerstone of treatment for type 1 and advanced type 2 diabetes for decades. Advances in insulin therapy have included not only improving the source and purity of the hormone, but also developing more physiological means of delivery.

Clearly, there are limitations that hinder normalizing blood glucose using insulin alone. First, exogenously administered insulin does not mimic endogenous insulin secretion. In normal physiology, the liver is exposed to a two- to fourfold increase in insulin concentration compared to the peripheral circulation.

In the postprandial state, when glucagon concentrations should be low and glycogen stores should be rebuilt, there is a paradoxical elevation of glucagon and depletion of glycogen stores. As demonstrated in the Diabetes Control and Complications Trial and the United Kingdom Prospective Diabetes Study,intensified care is not without risk.

In both studies, those subjects in the intensive therapy groups experienced a two- to threefold increase in severe hypoglycemia. Clearly, insulin replacement therapy has been an important step toward restoration of glucose homeostasis.

But it is only part of the ultimate solution. The vital relationship between insulin and glucagon has suggested additional areas for treatment. With inadequate concentrations of insulin and elevated concentrations of glucagon in the portal vein, glucagon's actions are excessive, contributing to an endogenous and unnecessary supply of glucose in the fed state.

To date, no pharmacological means of regulating glucagon exist and the need to decrease postprandial glucagon secretion remains a clinical target for future therapies. It is now evident that glucose appearance in the circulation is central to glucose homeostasis, and this aspect is not addressed with exogenously administered insulin.

Amylin works with insulin and suppresses glucagon secretion. It also helps regulate gastric emptying, which in turn influences the rate of glucose appearance in the circulation.

A synthetic analog of human amylin that binds to the amylin receptor, an amylinomimetic agent, is in development. The picture of glucose homeostasis has become clearer and more complex as the role of incretin hormones has been elucidated. Incretin hormones play a role in helping regulate glucose appearance and in enhancing insulin secretion.

Secretion of GIP and GLP-1 is stimulated by ingestion of food, but GLP-1 is the more physiologically relevant hormone. However, replacing GLP-1 in its natural state poses biological challenges. In clinical trials, continuous subcutaneous or intravenous infusion was superior to single or repeated injections of GLP-1 because of the rapid degradation of GLP-1 by DPP-IV.

To circumvent this intensive and expensive mode of treatment, clinical development of compounds that elicit similar glucoregulatory effects to those of GLP-1 are being investigated.

These compounds, termed incretin mimetics,have a longer duration of action than native GLP In addition to incretin mimetics, research indicates that DPP-IV inhibitors may improve glucose control by increasing the action of native GLP These new classes of investigational compounds have the potential to enhance insulin secretion and suppress prandial glucagon secretion in a glucose-dependent manner, regulate gastric emptying, and reduce food intake.

Despite current advances in pharmacological therapies for diabetes,attaining and maintaining optimal glycemic control has remained elusive and daunting. Intensified management clearly has been associated with decreased risk of complications. Glucose regulation is an exquisite orchestration of many hormones, both pancreatic and gut, that exert effect on multiple target tissues, such as muscle, brain, liver, and adipocyte.

While health care practitioners and patients have had multiple therapeutic options for the past 10 years, both continue to struggle to achieve and maintain good glycemic control. There remains a need for new interventions that complement our current therapeutic armamentarium without some of their clinical short-comings such as the risk of hypoglycemia and weight gain.

These evolving therapies offer the potential for more effective management of diabetes from a multi-hormonal perspective Figure 3 and are now under clinical development. Aronoff, MD, FACP, FACE, is a partner and clinical endocrinologist at Endocrine Associates of Dallas and director at the Research Institute of Dallas in Dallas, Tex.

Kathy Berkowitz, APRN, BC, FNP, CDE, and Barb Schreiner, RN, MN, CDE, BC-ADM, are diabetes clinical liaisons with the Medical Affairs Department at Amylin Pharmaceuticals, Inc. Laura Want, RN, MS, CDE, CCRC, BC-ADM, is the clinical research coordinator at MedStar Research Institute in Washington, D.

Note of disclosure: Dr. Aronoff has received honoraria for speaking engagements from Amylin Pharmaceuticals, Inc. Berkowitz and Ms. Schreiner are employed by Amylin. Want serves on an advisory panel for, is a stock shareholder in, and has received honoraria for speaking engagements from Amylin and has served as a research coordinator for studies funded by the company.

She has also received research support from Lilly, Novo Nordisk, and MannKind Corporation. Amylin Pharmaceuticals, Inc.

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β-CELL HORMONES. α-CELL HORMONE: GLUCAGON. INCRETIN HORMONES GLP-1 AND GIP. AMYLIN ACTIONS. GLP-1 ACTIONS. Article Navigation. Feature Articles July 01 Glucose Metabolism and Regulation: Beyond Insulin and Glucagon Stephen L.

Aronoff, MD, FACP, FACE ; Stephen L. Aronoff, MD, FACP, FACE. This Site. Google Scholar. Kathy Berkowitz, APRN, BC, FNP, CDE ; Kathy Berkowitz, APRN, BC, FNP, CDE. Barb Shreiner, RN, MN, CDE, BC-ADM ; Barb Shreiner, RN, MN, CDE, BC-ADM. Laura Want, RN, MS, CDE, CCRC, BC-ADM Laura Want, RN, MS, CDE, CCRC, BC-ADM.

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