Week 1 Flashcards
(19 cards)
Why study insulin and carbohydrates?
- Organism’s living fundamental task is to get and use energy and insulin signaling (evolutionary benefit for divergent species including mammals, fish, worms, and flies) regulates energy use and storage. (IMPORTANT TO LIVE)
- Insulin has been used as a test case for molecular studies over the past 150 years. (one of the first proteins to be sequenced, crystallized, and used in a strategy for producing a protein from a GMO (genetically modified organism). [DEVELOPMENT OF BIOLOGY]
- Information from this course will help to develop knowledge on carbohydrate usage in the healthy state, under physiologically stressful conditions and in the diabetic state.
What happens in the absence of insulin?
-Glucose cannot enter the cell and makes high blood sugar in the body -That sugar flows out as urine (sweet urine) -Not being able to metabolize your sugar to energy –> weight loss, thirst, hunger, dehydration (due to high blod sugar) -Without any energy, the body turns to breaking down fat (ketogenesis - formation of ketone bodies). -High levels of ketones lead to acidification of blood and electrolyte imbalance (DKA - typically type 1).
Elaborate more about why DKA happens, symptoms, and what happens if left untreated.
- DKA happens typically when the body is under physiological stress (i.e. infection).
- The symptoms of DKA may initially be confused with a stomach flu: abdominal pain, nausea and vomiting, loss of appetite, kussmahl breathing (rapid, deep), mental confusion, acetone scented breath.
- It can lead to a coma and possibly death if untreated/failed to diagnose
- Another situation in which DKA can become fatal is when diabetics are imprisoned and cannot obtain prompt insulin treatment.
What type of breathing is associated with DKA?
-Kussmaul Breathing (deep, labored, and sweet breath) -This breathing is an attempt by the body to de-acidify the blood.
What happens when a healthy individual eats?
- The pancreas secretes insulin into the bloodstream
- Insulin acts on cells causing them to take up glucose from the bloodstream for metabolism.
- Insulin also inhibits cells from breaking down fatty acids.
What happens in Type 1 diabetes?
- the beta cells (which make insulin) of the pancreas are killed by an autoimmune response (genetic factor) and they can no longer make insulin.
- Age of onset: juvenile diabetes - peak ages b/w 10-14 yrs.
- New onset Type 1 diabetes can also occur in adults.
- Symptoms: DKA, xs nausea and vomiting, hyperglycemia (much higher than Type 2)
- Acute severity that is fatal w/o insulin
- Possibly due to viral trigger (environmental factor)
- Treatment: insulin
What happens in Type 2 diabetes?
- The person can make insulin but is resistant to the action of insulin on cells.
- Typically adult onset.
- A chronic condition as compared to Type 1 diabetes and can lead to complications of blindness, amputation, cardiovascular disease, and less effective immune system over time.
- typically happens as a consequence of high blood sugar over time. Risk for acute illness like DKA is less than in type 1 diabetes.
- Genetic: predisposition to less effective insulin signaling
- Environmental cause: bad diet and low physical activity
- Treatment: modifying diet and increasing exercise to restore insulin sensitivity. (LIFESTYLE). As the condition progresses, additional insulin may be prescribed.
- Sometimes, people may need drugs that lower blood sugar such as metformin.
What are the symptoms of diabetes?
- Frequent urination (polyuria),
- increased drinking (polydipsia) and eating (polyphagia) -weight loss,
- dehydration,
- weakness/tiredness,
- dizziness,
- blurred vision,
- slow wound healing,
- red and inflamed gums.
What are the instances where diabetes was recognized as a disease?
- (1550 BCE)Ebers Papyrus ref “shrunken” patient, xs urination, and xs thirst (possible ref to person w/ diabetes.)
- (100AD) Aretaeus of Cappadocia ref wasting disease and polyuria. He coined “diabetes” - to siphon through.
- (400AD)Sushruta wrote urine tasted sweet; noted congenital (probs Type 1) form and later onset (probs Type 2) form.
- (1500) Paracelsus noted when the diabetic urine dried it left white powder and proposed this “salt” caused kidney irritation and was the cause of the excess urination.(wrong.)
- (1600s) Willis noted that diabetic urine was sweet. Named disorder “Diabetes mellitus” to distinguish it from “Diabetes insipidus”. (latter increased urination but urine does not contain excess sugar; latter caused by misregulation of kidney function.)
When did scientists determine the Importance of pancreas in the development of diabetes; endocrine secretion hypothesis?
- Dobson treated Dickenson who came to him DM symptoms. Dobson found blood was not as sweet as the urine’s white powder. Dobson’s finding of blood sugar significant b/c DM was not a defect only in kidneys but rather indicated a more systemic problem with the utilization of food.
- (1709)Brunner removed pancreas from 8 dogs and found this caused the dogs to xs urinate xs thirst. Despite observing these symptoms, he did not make the connection to diabetes.
****(1889) Minkowski and Mering did similar Brunner dog exp. But they proposed that diabetes was caused by this defect in the pancreas.
- (1893)Hedon removed the pancreas from dogs but left behind a piece of pancreas under the skin and the dogs did not develop diabetes. Hedon inferred there was another internal or endocrine secretion made by the pancreas that was required for proper metabolism of sugar.
- Langerhans described patches of cells in the pancreas that were distinct from the acinar cells and that were not connected to the ducts. These “islands” of cells were named after him.
****(1901)Opie connected that the Islets of Langerhans were morphologically defective in patients with diabetes. Together these observations led to the hypothesis that the Islets of Langerhans, in the pancreas, produced some kind of internal secretion that prevented diabetes.
When did we think there was a dietary solution to diabetes?
- Most therapies for diabetes were palliative, meant to provide the patient comfort.
- Opium was often prescribed in this context.
- (1850s)Piorry prescribed extra sugar in the diet of diabetics. He reasoned that this would replace sugar lost in the urine and would prevent the wasting seen in patients with diabetes. Increased sugar in the diet only made the patients worse –it increased their blood sugar and hastened their death.
- (1870s)Bouchardat observed that glycosuria (sugar in the urine) disappeared among diabetics were subject to rationing. He also noted that exercise increased the tolerance of diabetics to carbohydrates.
- Frederick Allen developed a treatment plan for diabetics that involved strict caloric/carbohydrate restrictions until the urine cleared of sugar. Calories were then added to the point just below which sugar accumulated again. The Allen diets succeeded in keeping the patients alive. It also relieved much of the excessive thirst and urination. However, patients could not live past a few years on what was essentially a starvation diet.
When was there a hunt for a pancreatic extract to cure diabetes?
- The notion that an extract made from pancreas could potentially cure diabetes had its origins in a/ the inference that the pancreas produced some sort of endocrine substance and b/ the precedent that thyroid extracts, when fed to patients, could cure them of hypothyroidism.
- Feeding pancreas pieces to diabetics failed to relieve their symptoms. This makes sense since insulin, unlike thyroxin, is a peptide hormone and would have been broken down by the digestive system. (DON’T EAT IT, INJECT IT!)
- Zulezer injected pancreatic extracts into rabbits along with adrenalin (increase blood sugar) to see if the extracts could counter the effects of adrenalin on blood sugar. He had positive results in these exp as well as in experiments in which he injected extracts into dogs from which the pancreas had been removed. He also injected the pancreatic extracts into a severely ill human patient and noted temporary, dramatic improvement. Zuelzer’s efforts at developing a pancreas extract that could be used therapeutically were hampered by 1/ toxic side effects of his extracts and 2/ no $$$
- Banting and Best were able to lower the blood sugar of a pancreatectomized dog. Under the supervision of Dr. MacLeod, they continued their experiments with the assistance of Collip, an experienced biochemist. The first attempt at using pancreatic extract (made by Banting and Best) on a human was tried in early January 1922 and failed. An extract made by Collip later that same month was tried on the same patient successfully.
What else did Collip do?
Important concept from the reading:
-Collip developed a bioassay for insulin that did not require the time consuming production of dogs with diabetic symptoms (i.e. depancreatized dogs). He realized that pancreatic extracts could lower the blood sugar of intact rabbits to the point where the rabbits went into hypoglycemic shock. He defined one unit of insulin as the amount of insulin that would lower the rabbit’s blood glucose by half. With a more efficient bioassay, he could test more extracts. This allowed him to systematically vary the extraction conditions. He found that the active compound (insulin) was extracted and soluble up to 90% ethanol but that the active compound was insoluble above 95% ethanol. He used this information to first raise the ethanol concentration to 90%. He then removed all of the precipitated, unwanted cell debris by filtration, keeping the liquid that flowed through the filter. He then raised the ethanol concentration in this liquid extract to 95%. This caused the insulin to precipitate. He then poured off the liquid portion of the extract, keeping the precipitate which he could later resuspend in his solvent of choice.
What is the anatomy of the pancreas?
- Acinar cells secrete digestive enzymes into pancreatic ducts which deposit the secretions in the duodenum
- Pancreatic islets contain beta cells (insulin-producing) and alpha cells (glucagon-producing)
- Insulin and glucagon are transported from the islets to the rest of the body through the blood supply
- The capillaries in the pancreas have endothelial cells with fenestrations, which enhance the ability of small molecules to travel in and out of the bloodstream.
What is the concept of honeymoon?
- In Type 1 diabetes, symptoms of diabetes are not noted until the beta cells in the pancreas reach about 20% of normal function.
- This may be many weeks, months or even a few years after the immune system initially begins attacking the beta cells. -Type 1 diabetics then typically are still producing some insulin when they are first diagnosed.
- Treatment with insulin often is accompanied by a “revival” of beta cells which then resume making more insulin.
- This leads to a “honeymoon” period (typically lasting months) in which the diabetic needs much less insulin.
- The honeymoon unfortunately never lasts, the beta cells ultimately all fail, and the individual becomes completely dependent on insulin to stay alive.
- Lack of injected insulin in Type 1 diabetics leads to death in days to weeks.
Describe levels of glucose in a normal body
- The concentration of glucose in the bloodstream in a healthy person is between 70 and 140 mg/dl ( 4 and 7.8 mM) depending on whether the person is fasting (low end) or has recently eaten a carbohydrate-containing meal (high end). This is an extraordinarily tight range given how much variation there is in our usage of glucose (high vs low activity) and our food intake (high vs low carb meals).
- This buffering of blood glucose is necessary to prevent glucose from dropping too low which would result in a hypoglycemic coma and also necessary from allowing glucose to accumulate to high levels associated with DKA (very high levels) or increased risk of cardiovascular and other long-term complications (moderately elevated levels over long time periods).
- Insulin is one of the hormones that is responsible for this buffering.
- It does so by acting on several processes in the body.
Describe glucose transport
- Glucose is transported from the bloodstream into cells by transporters of the GLUT gene family.
- The GLUT4 transporter is expressed in fat cells and in muscle cells and is regulated by insulin. At low blood sugars (and therefore low insulin levels) most of the GLUT4 transporters are located in vesicles inside the cell.
- As the blood sugar rises after a meal, insulin levels rise. Insulin binds to insulin receptors at the surface of the muscle or fat cell triggering the insulin signaling pathway in the cytoplasm of the cell.
- This causes the GLU4 containing vesicles to fuse with the membrane. The increased number of GLUT4 transporters can thus facilitate transport of glucose from outside the cell to the inside.
Describe GLUT transporters
GLUT transporters are members of the much larger family of Major Facilitator Superfamily of Membrane Transporters.
- GLUT transporters are uniporters meaning they bind to and transport only one molecule at a time across the membrane. -They are thought to do so through a kind of “rocker switch” mechanism in which the empty substrate binding site is initially exposed to the outside of the cell.
- Upon substrate (in this case glucose) binding, the GLUT protein changes conformation, exposing the substrate binding site and bound substrate to the inside of the cell. –Release of the substrate into the cytoplasm is followed by return of the GLUT transporter to its original state with the binding site facing the outside of the cell.
- GLUT4 transporters facilitate transport of glucose from regions of high concentration (outside the cell) to regions of low concentration (inside the cell).
How does glucose stay in the cell?
Once inside the cell, glucose is phosphorylated by hexokinase to form glucose-6-phosphate (G6P). G6P cannot leave the cell. This “trapped” glucose can then be used by the body to make glycogen in muscle, a storage form of glucose that can be rapidly broken down, or fat in fat cells, a more long term energy storage solution.
