Life 102 - week 8 - Obesity, diabetes and exercise
Ghrelin
A hunger-arousing hormone secreted by an empty stomach
Diabetic ketosis results when insulin is absent - Why is this?
Because we don't have insulin, we cant absorb glucose. So no glucose is going into the liver, adipose tissue or muscle. Unfortunately what happens is the adipose tissue release fatty acids because it thinks the body needs another fuel. Doesn't have any glucose so therefore I'll give the body some fatty acids. The fatty acids then go to the liver, The liver then degrades the fatty acids by oxidation but cannot process the acetyl CoA, because of a lack of glucose- derived oxaloacetate ( OAA). Excess ketone bodies are formed and released into the blood. Example of a ketone body that may be formed is acetate, that eventually causes acidosis as these ketones are acids that lower the pH of the blood. And if left untreated you will fall into a coma and die.
Type 2 diabetes accounts for approximately 90% of the diabetes cases throughout the world and is the most common metabolic disease in the world. Type two diabetes is the leading cause of--
Blindness, kidney failure and amputation in America
What convenient method can be used to determine whether you are overweight or obese
Calculating your body mass index
We begin our consideration of the effects of disruptions in caloric homeostasis with diabetes mellitus, a complex disease which is characterised by?
Diabetes mellitus is characterized by overproduction of glucose by the liver and inability of other tissues to use glucose. a complex disease characterized by grossly abnormal fuel usage: glucose is overproduced by the liver and underutilized by other organs.
Recall that the First Law of Thermodynamics states that energy can neither be created nor destroyed. Translated into the practical terms of our diets,
Energy consumed = energy expended + energy stored
Excess fat in the peripheral tissues can lead to insulin resistance how?
Excess fat accumulation in peripheral tissues, most notably muscle, can disrupt some signal-transduction pathways and inappropriately activate others. In particular, diacylglycerols and ceramide activate stress-induced pathways that interfere with insulin signaling, resulting in insulin resistance. Indeed, the inability to process all of the fatty acids results in their reincorporation into triacylglycerols and the accumulation of fat in the cytoplasm. In the cytoplasm, levels of diacylglycerol and ceramide (a component of sphingolipids) also increase. Diacylglycerol is a second messenger that activates protein kinase C (PKC). When active, PKC and other Ser/Thr protein kinases are capable of phosphorylating IRS and reducing the ability of IRS to propagate the insulin signal. Saturated and trans unsaturated fatty acids may also activate kinases that block the insulin signal. Ceramide or its metabolites inhibit glucose uptake and glycogen synthesis, apparently by inhibiting PDK and Akt. The result is diet-induced insulin resistance.
When you eat as soon as the food starts to pass though your gut, it send signals to brain, to say hey there's food passing through and so the brains feeling full and telling the body it doesn't want to eat anymore. What are these satiety inducing signals?
GLP-1 ( glucagon like peptide 1) and Cholecystokinin (CCK)
What are example's of gut hormones that are released to encourage you to eat?
Ghrelin, secretion increases before a meal and decreases after a meal.
Oxaloacetate condenses with acetyl co a to form citrate. If their is no OAA in the liver, muscle or the brain you cannot do what?
Go through the Citric acid cycle. Oxaloacetate comes from a side reaction where pyruvate can convert directly into oxaloacetate, so ultimately oxaloacetate comes from glucose as glucose makes pyruvate and pyruvate makes oxaloacetate
Given its biochemical prominence, increased muscle activity—exercise—coupled with a healthy diet, is one of the most effective treatments for diabetes as well as a host of other pathological conditions. What is the biochemical basis of this?
If you exercise you create muscle and if you are exercising you are using that muscle and so releasing calcium regularly through contractions. This will increase the number of mitochondria that you have in your muscle cells, as calcium increases the expression of genes that will make mitochondria. This calcium will also increase the expression of enzymes that break down fatty acids. In concert, the increase in fatty acid oxidizing capability and additional mitochondria allow for the efficient metabolism of fatty acids. Because an excess of fatty acids results in insulin resistance, as already discussed, efficient metabolism of fatty acids results in an increase in insulin sensitivity.
How does insulin work? encourage the uptake of glucose and reduction of blood sugars after we have eaten?
In a normal cell, insulin binds to its receptor, which then auto phosphorylates on tyrosine residues, with each subunit of the receptor phosphorylating its partner. Phosphorylation of the receptor generates binding sites for insulin-receptor substrates (IRSs), such as IRS-1. Subsequent phosphorylation of IRS-1 by the tyrosine kinase activity of the insulin receptor engages the insulin-signaling pathway (1). Phosphorylated IRS-1 binds to phosphoinositide 3-kinase (PI3K) and activates it. PI3K catalyzes the conversion of phosphatidylinositol 4,5-bisphosphate (PIP2) into phosphatidylinositol 3,4,5-trisphosphate (PIP3), a second messenger (2). PIP3 activates the phosphatidylinositol-dependent protein kinase (PDK) (3), which in turn activates several other kinases, most notably Akt (4), also known as protein kinase B (PKB). Akt facilitates the translocation of the glucose transporter (GLUT4)-containing vesicles to the cell membrane, which leads to a more robust absorption of glucose from the blood. Moreover, Akt phosphorylates and inhibits glycogen synthase kinase (GSK3). Recall that GSK3 inhibits glycogen synthase (Section 21.5). Thus, insulin leads to the absorption of glucose from the blood, activation of glycogen synthase, and enhanced glycogen synthesis.
How does insulin resistance lead to failure of the β cells of the pancreas that results in type 2 diabetes?
In order to get full-blown type two diabetes, you have to start killing your pancreatic b cells. Recall that, under normal circumstances, the β cells of the pancreas synthesize large amounts of proinsulin. The proinsulin folds into its three-dimensional structure in the endoplasmic reticulum and is processed into insulin, and is subsequently packaged into vesicles for secretion. As insulin resistance develops in the muscle, the β cells respond by synthesizing yet more insulin in a futile attempt to drive insulin action. The ability of the endoplasmic reticulum to process all of the proinsulin and insulin becomes compromised, a condition known as endoplasmic reticulum (ER) stress, and unfolded or misfolded proteins accumulate. ER stress initiates a signal pathway called the unfolded protein response (UPR), a pathway intended to save the cell. UPR consists of several steps. First, general protein synthesis is inhibited so as to prevent more proteins from entering the ER. Second, chaperone synthesis is stimulated. Recall that chaperones are proteins that assist the folding of other proteins (Section 2.6). Third, misfolded proteins are removed from the ER and are subsequently delivered to the proteasome for destruction. Finally, if the described response fails to alleviate the ER stress, programmed cell death is triggered, which ultimately leads to β cell death and full-fledged type 2 diabetes.
Causes of Type 1 Diabetes Mellitus
In type 1 diabetes, insulin production is insufficient because of autoimmune destruction of the β cells of the pancreas. Consequently, the glucagon/insulin ratio is at higher-than-normal levels. In essence, the diabetic person is in biochemical fasting mode despite a high concentration of blood glucose. Because insulin is deficient, the entry of glucose into adipose and muscle cells is impaired. The liver becomes stuck in a gluconeogenic and ketogenic state. The gluconeogenic state is characterized by excessive production of glucose. The excessive level of glucagon relative to that of insulin leads to a decrease in the amount of fructose 2,6-bisphosphate (F-2, 6-BP), which stimulates glycolysis and inhibits gluconeogenesis in the liver. Hence, glycolysis is inhibited and gluconeogenesis is stimulated because of the opposite effects of F-2, 6-BP on phosphofructokinase and fructose-1, 6-bisphosphatase (Section 16.4; Figure 27.9). Essentially, the cells' response to a lack of insulin amplifies the amount of glucose in the blood. The high glucagon/insulin ratio in diabetes also promotes glycogen breakdown. Hence, an excessive amount of glucose is produced by the liver and released into the blood. Glucose is excreted in the urine (hence the name mellitus) when its concentration in the blood exceeds the reabsorptive capacity of the renal tubules. Water accompanies the excreted glucose, and so an untreated diabetic in the acute phase of the disease is hungry and thirsty. Because carbohydrate utilization is impaired, a lack of insulin leads to the uncontrolled breakdown of lipids and proteins, resulting in the ketogenic state. Large amounts of acetyl CoA are then produced by β oxidation. However, much of the acetyl CoA cannot enter the citric acid cycle, because there is insufficient oxaloacetate for the condensation step. A striking feature of diabetes is the shift in fuel usage from carbohydrates to fats; glucose, more abundant than ever, is spurned. In high concentrations, ketone bodies overwhelm the kidney's capacity to maintain acid-base balance. The untreated diabetic can go into a coma because of a lowered blood-pH level and dehydration. Interestingly, diabetic ketosis is rarely a problem in type 2 diabetes because insulin is active enough to prevent excessive lipolysis in liver and adipose tissue.
Insulin also appears to decrease levels of appetite stimulating peptides?
Insulin is secreted by the β cells of the pancreas when blood-glucose levels are high. Insulin also appears to act in the brain to decrease levels of NPY and AgRP.
Insulin is a hormone that is released by beta cell of the pancreas and reports on the?
Insulin reports on the status of glucose in the blood—in other words, of carbohydrate availability.
Two key signal molecules regulate energy homeostasis over long term (time scale of hours or days) are?
Leptin and insulin
Function of leptin in terms of caloric homeostasis?
Leptin is secreted by the adipocytes in direct proportion to the amount of fat present. The more fat in a body, the more leptin is secreted. Leptin binding to its receptor throughout the body increases the sensitivity of muscle and the liver to insulin, stimulates β oxidation of fatty acids, and decreases triacylglycerol synthesis.
Leptin which is a hormone secreted by the adipocytes reports on the what status of the cell?
Leptin reports on the status of the triacylglycerol stores of the cell
What is the molecular basis of leptin resistance>
Leptin resistance may result from the inappropriate activation of proteins called suppressors of cytokine signaling (SOCS). In the case of insulin, and most likely leptin, SOCS bind to phosphorylated tyrosine residues and disrupt the signal-transduction pathway.
Leptinin action when eating?
Long term signal, so isn't something that happens in response to eating immediately, takes a bit of time. - So you eat and that eventually leads to more fat cell mass. - Because fat cell mass has gone up we get an increase in leptin expression so more leptin is produced. - This leads to an increase in leptin action in the hypothalamus. - Leptin binds to its receptor, thereby activating a signal transduction pathway. The leptin receptor is found in various regions of the brain, but particularly in the arcuate nucleus of the hypothalamus. - Leptin, inhibits the NPY/AgRP neurons, preventing the release of NPY and AgRP and thus repressing the desire to eat. Therefore decreasing food intake. - On the other hand Leptin activates POMC producing neurons, which leads to and increase in expression of (MSH) Melanocyte stimulating hormone which activates appetite-suppressing (anorexigenic) neurons and thus inhibits food consumption. Thus, the net effect of leptin binding to its receptor is the initiation of a complex signal-transduction pathway that ultimately curtails food intake.
Treatmemts fro type two diabetes?
Most are behavioral in nature. Diabetics are advised to count calories, making sure that energy intake does not exceed energy output; to consume a diet rich in vegetables, fruits, and grains; and to get plenty of aerobic exercise. For those who are not able to maintain proper glucose levels with the behaviors described herein, drug treatments are required. The administration of insulin may be necessary upon pancreatic failure, and treatment with metformin (Glucophage), which activates AMPK, may be effective. AMPK promotes the oxidation of fats, while inhibiting fat synthesis and storage. It also stimulates glucose uptake and storage by muscle while inhibiting gluconeogenesis in the liver. People use this drug to try to find another way to start to absorb glucose and start to store it and this lower those blood glucose levels.
What is one of the most significant predisposing factors for type 2 diabeties?
Obesity
health consequences of obesity
Obesity is identified as a risk factor in a host of pathological conditions including diabetes mellitus, hypertension and cardiovascular disease, dyslipidaemia, strokes, certain cancers such as colon, liver and gallbladder disease, sleep apnoea and respiratory problems, osteoarthritis and gynaecological problems such as infertility . The cause of obesity is quite simple in most cases: more food is consumed than is needed, and the excess calories are stored as fat.
Caloric homeostasis is a means of regulating what?
Our body weight
Why the obesity epidemic is occurring in the first place?
Overlapping possible explanations: 1.Our bodies are programmed to store excess calories in case food becomes scarce. 2.Leaner individuals may have avoided predation. Since the risk of predation has declined, the advantage of leanness has also declined. 3.Highly palatable foods may be acting as drugs, stimulating reward pathways in the brain that are triggered by drugs such as cocaine. These reward pathways can be strong enough to override appetite-suppressing signals 4.Changes in our gut microbiome may facilitate the accumulation of excess calories. - For instance, germ-free mice do not become obese, even when given unfettered access to a high-fat diet. However, when such mice are exposed to the intestinal flora of obese mice, the mice now become obese even on a normal chow diet. Moreover, the intestinal microbiome of obese mice triggers an inflammatory response that may blunt the effect of signal molecules that normally regulate the desire to eat as well as how the mice process the calories they consume. Many of these results have been extended to humans. 5.Genetic differences alter how individuals respond to obesity-inducing environmental conditions.
Dieting can be used to combat obesity, Some evidence suggests that low carbohydrate-high protein diets may be effective for weight loss why is this?
Proteins seem to induce a feeling of satiation more effectively than do fats or carbohydrates. Proteins require more energy to digest than do fats or carbohydrates, and the increased energy expenditure contributes to weight loss. The best means to lose weight is to eat less/better and exercise more.
Because in diabetes people cannot absorb glucose into their liver, they cannot make --
Pyruvate, as we don't have any glucose to to start glycolysis. Similarly if we don't have pyruvate we cant make oxaloacetate, and if we don't have this we cant start the citric acid cycle
When you eat, short term signals such as Cholecystokinin (CCK) and glucagon-like peptide 1 (GLP-1) , relay feelings of what?
Satiety from the gut to various regions of the brain to reduce the urge to eat.
More sicnietifc explanation of how these short term signals induce feelings of satiety?
Short-term signals relay feelings of satiety from the gut to various regions of the brain and thus reduce the urge to eat . The best-studied short-term signal is chole-cysto-ki-nin (CCK). Cholecystokinin is actually a family of peptide hormones of various lengths (from 8 to 58 amino acids in length, depending on posttranslational processing) secreted into the blood by cells in the duodenum and jejunum regions of the small intestine as a postprandial satiation signal. The CCK binds to the CCK receptor, a G-protein-coupled receptor located in various peripheral neurons, that relay signals to the brain. This binding initiates a signal-transduction pathway in the brain that generates a feeling of satiety. CCK also plays an important role in digestion, stimulating the secretion of pancreatic enzymes and bile salts from the gallbladder. Another important gut signal is glucagon-like peptide 1 (GLP-1), a hormone of approximately 30 amino acids in length. GLP-1 is secreted by intestinal L cells, hormone-secreting cells located throughout the lining of the gastrointestinal tract. GLP-1 has a variety of effects, all apparently facilitated by binding to its receptor, another G-protein-coupled receptor. Like CCK, GLP-1 induces feelings of satiety that inhibit further eating. GLP-1 also potentiates glucose-induced insulin secretion by the β cells of the pancreas while inhibiting glucagon secretion.
How does insulin stop diabetes ketosis?
Signalling tissues to take up glucose curtails fatty acid mobilization by adipose tissue
Type 1 diabetes is also known as insulin dependant diabetes because?
The affected person requires the administration of insulin to live.
The amount of adipokine leptin produced depends on the amount of what?
The amount of body mass fat a person has, the more body fat a person has the greater the amount of leptin produced.
If leptin is produced in proportion to body-fat mass and leptin inhibits eating, why do people become obese?
The failure to respond to the appetite-suppressing (anorexi-genic) effects of leptin is called leptin resistance and may be a contributing factor in the development of obesity.
How doe these signals GLP-1 and (CCK) induce the feeling of the fullness?
They both bind to receptors in nerve cells and basically increase satiety and therefore decrease food intake and body mass. GLP-1 also activates pancreas to secrete insulin
Like all signal pathways, the insulin-signaling cascade must be capable of being turned off. How?
Three different processes contribute to the down-regulation of insulin signaling. First, phosphatases deactivate the insulin receptor and destroy a key second messenger. Tyrosine phosphatase IB removes phosphoryl groups from the receptor, thus inactivating it. The second messenger PIP3 is inactivated by the phosphatase PTEN (phosphatase and tensin homolog), which dephosphorylates it, forming PIP2, which itself has no second-messenger properties.
Tyep 1 diabteis is caused by what?
Type 1 diabetes, or insulin-dependent diabetes, is caused by autoimmune destruction of the β cells of the pancreas and usually begins before a person reaches twenty.
Type two diabetes is characterised by what?
Type 2 diabetes, the most common form of the disease, is characterized by insulin resistance. Most diabetics, in contrast, have a normal or even higher level of insulin in their blood, but they are unresponsive to the hormone, a characteristic called insulin resistance.
What helps us maintain the perfect balance of energy input= energy output?
When you eat a meal there are lots of signals going on to your brain. Gastrointestinal tract is sending of signals, the pancreatic b cells are sending out signals in the form of insulin and fat cells are also endocrine tissues which are also sending signals such as the hormone leptin. Basically because you eat it triggers the release of signals in the form of peptides and hormones that induce the feeling of satiety (fullness). Usually act in arcuate nucleus a group of neurons in the hypothalamus of the brain that basically receives these signals and makes you feel like you do not want to eat any more.
Insulin resistance starts with something called metabolic syndrome which is?
You are eating and etaing putting on loads of weight, bmi is way highr than it should be. Gets to the point where the fat cells cant take up any more fat- no more room for it. So excess triacylglycerols start to go into the organs, so start to get a fatty liver, fatty blood vesells, fatty pancreas e.t.c
neuropeptide Y (NPY) and agouti-related peptide (AgRP) are an example of what type of peptides?
appetite-stimulating (orexigenic) peptides
cause of obesity
consuming more calories than (expending)
Leptin action when fasting?
fasting- less leptin expressed - Decrease in body fat cell mass - Decrease in leptin expression (amount of leptin produced) - Therefore decrease in leptin action in hypothalamus particular in arcuate nucleus of the hypothalamus. - Activation of neurons that express the appetite stimulating peptides NPY and AgRP. -Resulting in increase in NPY and AgRP expression, thus increasing the desire to eat and as a result increase in food intake. -Decrease in leptin levels also inhibits POMC producing neurons. - So leads to decrease in expression of MSH expression and therefore and increase hunger levels and as a result an increase in food intake.
caloric homeostasis ?
the ability to maintain adequate but not excessive energy stores
If we consume more energy than we expend this leads to what?
us becoming overweight or obese
Where is leptin secreted
•Adipose tissue, which is an active endocrine tissue
