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Manna Research is looking for individuals with Type 2 Diabetes to participate in a clinical research trial to help control blood sugar levels. We have over 40 years of combined & trusted experience conducting clinical research studies to thoroughly test new medications or medical devices for safety and efficacy. In the first of two lectures on the mobilisation of food reserves, we will consider some of the short-term mechanisms that normally provide energy to the body. Many different kinds of serpentine hormone receptor located in the plasmalemma signal via heterotrimeric G proteins, all of which require GTP. Gs and Gq are separate varieties of stimulatory Ga subunits activate two important signalling pathways: adenyl cyclase and phospholipase C.
Adenyl cyclase is an enzyme that is normally bound to the inner surface of the plasmalemma where it converts tiny amounts of ATP into 3'5' cyclic AMP.
Phospholipase C (PLC) is also bound to the plasmalemma where it hydrolyses inositol containing phospholipids to yield the water soluble inositol triphosphate (IP3) and diacylglycerol (DAG), which is hydrophobic and remains within the membrane.
Gi is an inhibitory Ga subunit that blocks the action of adenyl cyclase and is involved in a2 adrenergic signalling systems.
Protein kinase A: (PKA) is the "original" cyclic AMP dependent protein kinase, that was first identified in connection with glycogen metabolism, and is now known to phosphorylate dozens of proteins involved in b adrenergic signalling.
Protein kinase B: (PKB) is a phosphatidyl inositol 3,4,5 triphosphate (PIP3) dependent protein kinase, which is involved in insulin signal transduction. Protein kinase C: (PKC) is a calcium-dependent protein kinase that is normally bound to the inner surface of the plasmalemma and also requires diacylglycerol. Protein kinase G: (PKG) is a cyclic GMP dependent protein kinase which is believed to mediate many of the actions of cyclic GMP.
There are two different kinds of AMP, which is confusing for students because they are both involved in signalling.
In the previous lecture we considered linear 5' AMP which is in equilibrium with ATP and ADP via the myokinase reaction in the mitochondrial intermembrane space, and which activates the important regulatory enzyme AMPK. In this lecture we will consider 3'5' cyclic AMP, which is formed by adenyl cyclase in the plasmalemma under the control of G proteins.
It is possible to distinguish four main classes of catecholamine receptor through their differing sensitivities to agonists and inhibitors.
Sympathetic nerves and circulating adrenalin activate mobilising lipase in adipose tissue, by the classical mechanism involving b3 receptors, Gs, adenyl cyclase, cAMP and PKA. These two enzymes catalyse a potentially futile cycle, and are regulated in a reciprocal fashion. Hormones such as glucagon and adrenalin that promote glycogen breakdown act partly via cyclic AMP and protein kinase A.
Liver (L-type) and muscle (M-type) PFK subunits form mixed tetramers, but the genes are on separate chromosomes and their relative importance varies in different tissues.
In addition to the allosteric regulation by 5'AMP and citrate, PFK is strongly activated by fructose-2,6-bisphosphate which is produced by a second enzyme called phosphofructokinase-2 (PFK2). PFK2 is known as "tandem enzyme" because it also possesses fructose-2,6-bisphosphatase activity. The residual expression of FBPase in non-gluconeogenic tissues such as skeletal muscle suggests that some FBPase activity is important for normal PFK regulation.
Insulin increases PFK gene expression in the longer term and PFK activity is depressed in type 1 diabetics. These enzymes also catalyse a potential futile cycle, although it is a more circuitous process than the examples considered above. A lipolytic - gluconeogenic state, dominated by adrenalin and glucagon, with HIGH cyclic AMP.
The pyruvate kinase variant expressed in liver tissue has an extended amino acid sequence that is a substrate for protein kinase A.
In addition, expression of the cytosolic PEPCK gene is strongly and rapidly induced by cyclic AMP. One of the main aims of diabetes treatment is to keep blood glucose levels within a specified target range. Over time your readings will provide you and your health professionals with the information required to determine the best management strategy for your diabetes.
Self-blood glucose monitoring allows you to check your blood glucose levels as often as you need to or as recommended by your doctor or Credentialled Diabetes Educator. Blood glucose meters are usually sold as kits giving you all the equipment you need to start.
To test your blood glucose levels, you prick your finger with the lancet and add a small drop of blood onto a testing strip.
Keeping a record of your blood glucose levels can be very helpful for you and your doctor or Credentialled Diabetes Educator. Even though your meter may have a memory, it is important to keep a record of your readings in a diary and to take this with you to all appointments with your diabetes health team. Most meters on the market have software which allows you to download your records in different formats such as graphs and charts. Regular testing and recording of your blood glucose level can reinforce your healthy lifestyle choices as well as inform you of your response to other choices and influences. Importantly, blood glucose level pattern changes can alert you and your health care team to a possible need for a change in how your diabetes is being managed.

Better understand the relationship between your blood glucose levels and the exercise you do, the food you eat and other lifestyle influences such as travel, stress and illness. Know when to seek the advice of your diabetes health team about adjusting your insulin, tablets, meal or snack planning when blood glucose goals are not being met. There will be times when you need to test more often, however you should first discuss this with your doctor or Credentialled Diabetes Educator.
Your Credentialled Diabetes Educator can help you work out a testing plan especially for you. Effective management of diabetes is all about aiming for a careful balance between the foods you eat, how active you are and the medication you take for your diabetes. 2 Targets are as recommended by the NHMRC, Blood Glucose Control in Type 2 Diabetes, (2009). Sometimes you may get a lower or higher blood glucose reading than usual and you may not be able to figure out the reason. Contact your doctor or Credentialled Diabetes Educator if you notice that your blood glucose patters change or are consistently higher or lower than usual.
The accuracy of all meters can be checked with meter-specific liquid drops called control solutions. Many hospitals have a diabetes clinic where you can find out more about blood glucose monitoring. We are one of the largest networks of fully-owned and integrated outpatient clinical research sites in North America. These are of particular importance in the metabolic adaptation to physical exercise, which may start suddenly and without warning. PIP3 is a phospholipid within the plasmalemma: do not confuse it with inositol triphosphate (IP3) which is a water soluble second messenger. These receptor proteins are the products of different genes, and differ in their signalling mechanisms.
In white adipose tissue this results in the release of free fatty acids and glycerol into the bloodstream, but in brown adipose tissue the free fatty acids uncouple the mitochondria and the lipids are oxidised in situ. Both enzymes can be converted between active and less active forms using a system of protein kinases.
PKA phosphorylates and activates another protein kinase called phosphorylase b kinase, which in turn activates glycogen phosphorylase. In addition to the b effects mediated via cAMP, a1 agonists (and several other signals) also promote glycogen breakdown by raising the intracellular calcium concentration, and activating phosphorylase by the calmodulin route. As previously explained in lecture 20, phosphorylated insulin receptor substrate 1 (IRS-1) activates PI-3 kinase, leading to the synthesis of the phospholipid PIP3 or phosphatidyl inositol 3,4,5 trisphosphate.
This was one of the first allosteric enzymes to be discovered and it is a major control point for the glycolytic pathway.
The remainder of this discussion applies mainly to liver cells, where the gluconeogenic pathway may be in operation, via fructose-1,6-bisphosphatase (FBPase). Conversely, fructose-1,6-bisphosphatase is inhibited by fructose-2,6-bisphosphate, which consequently sets the switch in favour of glycolysis, and blocks gluconeogenesis.
The ratio between the two antagonostic enzyme activities is controlled by adrenalin and glucagon via adenyl cyclase, 3'5' cyclic AMP and protein kinase A. Newsholme has suggested that a low level of futile cycling may be important for effective regulation at low glycolytic fluxes, and allows the pathway to be controlled with much smaller excursions in the concentrations of the allosteric effectors. Fructose bisphosphatase and PFK are reciprocally regulated, and corticosteroids antagonise the insulin effects, although the detailed molecular mechanisms have yet to be elucidated.
PEPCK is not expressed in most extra-hepatic tissues, so the "problem" is largely confined to the liver, where the regulation incorporates some special features that are described below. Phosphorylation inactivates liver pyruvate kinase, but the isoenzyme in other tissues is not regulated in this way.
This involves a nuclear protein called CREB (cyclic AMP response element binding protein) which is a substrate for protein kinase A. This is the product of a separate gene, located in the nucleus but delivering its ultimate product to the mitochondria, which is not regulated in the same way as the cytosolic version. Maintaining good blood glucose control is your best defence to reduce the chances of developing complications from diabetes. There are many different types, offering different features and at different prices to meet individual needs. This strip is then inserted into the meter, which reads the strip and displays a number – your blood glucose level. Your doctor or Credentialled Diabetes Educator will help you decide how many tests are needed and the levels to aim for.
This will provide both you and your diabetes health team with important information in deciding if and how your treatment may need to be adjusted. Even if you can do this, it is still helpful to keep a diary, not only for your tests but also details of your daily activities, the food you eat and other relevant information. However many people test more often, such as those using an insulin pump (CSII – continuous subcutaneous insulin infusion). Because this is a delicate balance, it can be quite difficult to achieve ideal control all the time. Target ranges may differ depending on your age, duration of diabetes, the type of medication you are taking and if you have any other medical problems.

When you are sick with a virus or flu, your blood glucose levels will nearly always go up and you may need to contact your doctor.
The best defence against this is to see a Credentialled Diabetes Educator to learn how to use your meter, prepare your lancing site and how to maintain your meter and equipment. Therefore it does not replace the tests you do yourself but is an added tool in giving the overall picture of your blood glucose management.
Your doctor or Credentialled Diabetes Educator can help you decide on a target that is both appropriate and realistic for your individual circumstances.
Many of them are based on catecholamine messengers and the autonomic nervous system, although the peptide hormone glucagon sometimes acts in a similar way. Contact with the hormone receptor plus ligand leads to the replacement of GDP by GTP and the dissociation of the trimer into free Ga subunits containing bound GTP and a pair of bg subunits. It is not just for catecholamines and it is much more complex than a pure emergency signal. Receptors for the peptide hormone glucagon also signal via the cyclic AMP system, so that many of the metabolic effects of glucagon are very similar to the catecholamines. This lipid indirectly activates protein kinase B, which converts glycogen synthase kinase 3 (GSK3) from the active to the non-active form.
Phosphorylation in the presence of cyclic AMP ensures that all the phosphoenolpyruvate generated by liver PEPCK will be diverted into the gluconeogenic pathway, where it can contribute to blood glucose, instead of being converted into fat or oxidised via the Krebs cycle, as would otherwise occur.
When phosphorylated, CREB binds to specific DNA sequences upstream of the cAMP regulated genes, and switches on transcription. Blood glucose monitoring can help you understand the link between blood glucose, food, exercise and insulin. Most of these are available from Diabetes Australia in your state or territory, pharmacies and some diabetes centres. There are a number of other common causes for blood glucose levels to increase or decrease. Direct delivery of neurotransmitters to particular target tissues via the autonomic nerves is of comparable importance to the systemic delivery of adrenalin via the blood.
The Ga subunits may be either stimulatory or inhibitory (depending on the signalling system) but they all possess an intrinisic GTPase activity which self-terminates their action.
IP3 releases calcium ions from intracellular stores, and these subsequently activate protein kinase C as explained below. At the same time, PKA also phosphorylates and inactivates glycogen synthase, which prevents the futile cycling of glucose 1 phosphate back into glycogen via UDP-glucose.
Phosphorylated GSK3 is not able to phosphorylate and inactivate glycogen synthase, leading to increased glycogen deposition in the presence of insulin. This helps to ensure a stable energy supply and to control the conversion of carbohydrates into Krebs cycle intermediates and fats, as explained in detail below. PFK and FBPase catalyse a potential futile cycle, and appropriate regulatory mechanisms are required. This enables adrenalin and glucagon to switch on gluconeogenesis in liver tissue and stablise the blood glucose concentration. This ensures that key cytosolic enzymes in the gluconeogenic pathway will be produced in appropriately larger amounts when hepatic glucose production is stimulated by cyclic AMP.
Your doctor or Credentialled Diabetes Educator can help you choose the meter that’s best for you, and your Credentialled Diabetes Educator or pharmacist can show you how to use your meter to get accurate results. Ask your doctor or diabetes educator how you can use a diary to help you to better manage your diabetes. Once the GTP has been hydrolysed, the Ga subunit must re-associate with a bg pair before the process can be repeated. The glycerol released from triglyceride stores is metabolised in the liver and becomes an important source of blood glucose.
However, I now have a secret weapon to conquer my fear of salad. I love red onions, and I love garlic. So the two together created a delicious flavor explosion in my mouth that I just have to share..
Determined to overcome my salad challenged attitude, I began looking at various recipes on the web for chopped salads, and using several as a guide (to which I added my own twist of course) I came up with this great tasting blend of fresh corn, black beans, olives, peppers and avocado.
But rest assured that this delicious looking AND TASTING vegan hamburger recipe will have you happy and feeling great about your cruelty free choice. Instead, you can join the party with something just as tasty, happy in your stance of cruelty free food choices.
And though most vegan cheeses aren’t QUITE the same as cow or goat milk based cheeses, there are many commercial brands and some home made versions which definitely fill the void.
The sender was raving about the fabulousness of this mac and cheese, which I have to admit got my attention. The part I didn’t like was burning my oven for two hours to cook four patties of wheat meat.
We were surprised that such a modestly priced mix passed our taste test for vegans and omnis with flying color and a five-star rating.

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