Lecture 14 Flashcards
(23 cards)
What can people do to reduce the risk of diabetes?
They should control their glucose levels through diet, exercise, insulin, and other diabetic medications. Weight control, blood pressure control, lipid/cholesterol control, as well as stopping smoking.
What are the ABCs of diabetes treatment, and what can people with diabetes do to reduce the risk?
A: A1C levels measured at least twice a year
B: Blood pressure monitoring and control
C: Cholesterol monitoring and control
By constantly monitoring these levels, people with diabetes are able to reduce their risk for heart disease and stroke. The reason for this is that there can be complications for blood clotting for individuals with diabetes if they do not control their diabetes properly.
Review: Explain the ominous octet.
1) increase in lipolysis: breakdown of fats leads to ketone body production because your body thinks it’s in starvation mode
2) increased glucose reabsorption by the kidneys: more glucose goes back into the blood
3) a decrease in glucose uptake by the muscles: no signal to take up glucose, so can’t decrease blood sugar
4) neurotransmitter dysfunction
5) increased liver (hepatic) glucose production: gluconeogenesis occurs to increase blood sugar
6) increased glucagon secretion from alpha cells of the pancrease: pushes more glucose into the blood by glycogen breakdown/gluconeogenesis
7) impaired insulin secretion from beta cells of the pancreas (can’t take glucose from the blood)
8) decreased incretin effect: intestine involved in the absorption efficiently and to help excrete some of it. Decreasing this increases blood glucose
Type 2 Diabetes is ______ in origin and is due to a defective _____ metabolism.
Multifactorial in origin and due to defective carbohydrate metabolism.
There are multiple different things that end up coming together that then lead to T2D, but overall this is due to issues with carbohydrate metabolism, stemming from not being able to respond to insulin.
How are plasma glucose concentrations determined by your body?
The amount of glucose that is circulating in your blood at any time is determined through your diet and through production by your liver, versus how much is actually being taken up by your other tissues.
How much sugar you take in and how much is produced by your liver - how much your tissues absorb = how much glucose you have circulating
Can people with T2D also have a deficiency in insulin production? What specifically makes these individuals resistant to insulin?
Yes, they do not respond effectively to insulin, they do not have enough receptors, their receptors are mutated, or something has gone wrong downstream of the pathway which impacts their ability to be able to lower blood sugar.
Insulin resistance is a central element of type 2 diabetes, and may be the result of what?
1) Genetic factors: having family members with T2D
2) Obesity: visceral fat can lead to development of T2D
3) Decreased physical fitness: leads to obesity and trigger onset of this disease
4) Glucose toxicity: having super high levels of glucose can affect receptor’s ability to respond to insulin
What are the 2 main classes of fat? Which fat do men have more of and why? Which fat is worse for you and why?
Subcutaneous fat: fat under the skin - women have more (when women gain weight, it’s evenly distributed around the body)
Visceral fat: fat surrounding organs and under abdominal muscles - more in men (when men gain weight, they usually form a belly). This is the bad fat (associated with insulin resistance.) It can release certain proteins and certain factors that can increase inflammation, increase blood clotting, increase issues with lipid circulation in the body and increase hypertension.
What protein gets released from visceral fat that has been shown to increase resistance to insulin?
Retinol-binding protein 4 (RBP4 has been shown to increase insulin resistance to insulin.
What is the most common oral medication for type 2 diabetes? How does it work?
Metformin works by leading to the activation of specific proteins that are going to tell your body that it needs energy. It will enter the mitochondria and act as an uncoupler to uncouple ATP synthase from ETC. it acts on complex 1, leading to a decrease in the proton gradient, and overall, less ATP production.
As ATP decreases, there is more AMP in the cell and leads to the activation of AMPK, a serine/threonine kinase, leading to the activation of specific genes/enzymes/pathways.
This increase in AMPK will phosphorylate enzymes like PFK to stimulate glycolysis, and FBPase-1 to inhibit gluconeogenesis. The decrease in ATP production is going to specifically activate pyruvate kinase and increase PFK activity.
Overall:
- Improved insulin receptor function
Improved glucose transport
- An increase in GLUT transporters at the surface of the cells
- A decrease in pathways involved in synthesis (and energy storage, including glycogen synthesis, fat synthesis, protein production).
- Decrease in glucagon response, thereby preventing further increases in blood sugar as a result of gluconeogenesis/glycogen breakdown in the liver.
- Overall improved insulin sensitivity (more glucose, better response to the insulin receptor, and will tell your body you can respond to insulin a bit better).
What does metformin do to glucagon receptors in hepatocytes? Why?
Use of metformin to uncouple complex 1 from ATP synthase decreases energy/ATP production which increases AMP concentrations in the cell, leading to the activation of AMPK so that cells can be more sensitive to insulin. Since the insulin response is active/stimulated, glucagon responses should not be - therefore lowering blood sugar.
What were the effects of early thiazolidinedione use of diabetic patients, specifically on their HbA1C levels? Was the effect of HbA1C levels good/bad/not significant? Explain.
After diabetic patients had switched to pioglitazone, their HbA1C levels dropped significantly after 6 months to 3 years. This is a good thing because this shows that their hemoglobin is less glycolated, and thus these individuals are more able to manage their blood glucose levels.
What are incretins, and what do they do to affect blood sugar levels after eating?
Incretin: peptide gut hormones
1) Glucagon-like peptide 1 (GLP-1)
2) Gastric Inhibitory Polypeptide (GIP or glucose-dependent insulinotropic polypeptide)
After digesting food, it will reach the GI tract and the intestines are responsible for releasing these incretins. They will go into circulation, which will then affect both the beta and alpha cells (stimulates an increase in insulin secretion from the beta cells and will decrease glucagon secretion from alpha cells.)
After you have eaten, insulin levels should go up because blood sugar levels have gone up. By the time your energy reaches your intestines, you are going to want to be able to use some of this energy. If insulin is secreted, this will lead to glucose uptake by the muscles and inhibit glycogen breakdown, thereby leading a decrease in blood sugar.
What happens to the incretins over time? What inhibits these protein hormones? Why might this be an issue for individuals who suffer from diabetes, and what can be done to prevent the inhibition of these incretins?
Over time, an enzyme called DPP-4 will bind to Glucose-Dependent Insulinotropic Peptide (GIP) and Glucagon-Like Peptide I (GLP-1,) cleave them, and then break them down.
For people suffering from diabetes, they do not want DPP-4 to be active because this limits their body’s ability to be able to regulate blood sugar levels. In order to have these incretins active, there needs to be an inhibitor present for this DPP-4 enzyme.
On top of their role in stimulating beta cells and inhibiting alpha cells to lower blood sugar levels, what other roles do the incretins (GLP-1 and GIP) have?
GIP and GLP-1 also delay gastric emptying and increasing satiety. This is why after we eat, we don’t have to eat for a while because these incretins help with satiety, help with the leptin response, and help your body know that you are digesting food.
What role do the kidneys play in glucose control, and where in the kidney cells does this occur?
The kidneys reabsorb glucose. All the glucose/sodium is reabsorbed in the proximal tubules by Sodium-Glucose Cotransporters (SGLTs).
SGLT2: comes first, reabsorbs most of the glucose from filtrate/blood as it moves through the nephron
SGLT1: comes after and reabsorbs anything else from the filtrate that is in a later portion of the nephron/proximal tubule
How is glucose filtration in the kidneys different between normal/non-diabetic individuals and individuals with diabetes? In order to resolve the issue of glucose filtration for individuals with diabetes, what must occur?
By the time the filtrate gets to the rest of the tubule and through the collecting duct, there should not be any glucose left over in the filtrate.
However, if you are diabetic, you may start secreting some glucose through the urine, in which it will start to smell sweet/fruity as a result of higher glucose levels in the blood. This indicates a kidney problem.
However, lowering blood glucose in important, so SGLT2 should be inhibited by SGLT2 inhibitors, such that most of the glucose is excreted through urine and not reabsorbed.
What are the effects of taking an SGLT2 inhibitor, and how is this beneficial for individuals who have type II diabetes?
Taking an SGLT2 inhibitor will lead to the inhibition of renal tubular sodium-glucose cotransporters. This will lead to a reversal of hyperglycemia and decrease the effects of glucose toxicity.
Taking an SGLT2 inhibitor has been shown to:
- increase insulin signals overall
- increase insulin sensitivity in the muscle: leads to an increase in GLUT4 translocation)
- Increase beta cell function
- increase insulin sensitivity in the liver, leading to a decrease in gluconeogenesis
Other types of oral medications for T2D, like sulfonylureas and meglitinides, increase insulin secretin. Why might increasing insulin secretion be problematic?
For the medications to work, you need to have functioning beta cells which can produce insulin and have to be able to respond to insulin in the first place.
How do alpha-glucosidase inhibitors function to lower blood sugar? What do bile acid sequestrants and dopamine-2 agonists do?
Alpha-glucosidase inhibitors stop your body from absorbing glucose in your intestines.
Bile acid sequestrants were used to decrease bile acid, but it also lowers type 2 diabetics.
Dopamine-2 agonists lowers blood glucose.
Where do SGLT2 inhibitors, GLP-1 and GIP, DPP=4 inhibitors, thiazolidinediones, metformin, insulin, and amylin act in the body in order to reduce risk from diabetes?
- SGLT2 inhibitors act in the kidneys to prevent glucose uptake by the sodium-glucose cotransporters.
- Incretins (glucose-like peptide-1 and glucose-dependent insulinotropic polypeptide) work to inhibit glucagon secretion (alpha cells of pancreas) and work to stimulate insulin secretion (beta cells of pancreas) as well as inhibiting the liver from increasing blood sugar (glycogen breakdown and gluconeogenesis) and preventing fatty acid breakdown as well (to prevent ketone body circulation in the blood), in addition to helping with neurotransmitter dysfunction.
- DPP-4 inhibitors act on DPP-4 to prevent degradation of the incretins (such that the incretins can stimulate the insulin response, prevent glucagon from being secreted, and thus preventing gluconeogenesis and glycogen breakdown from occurring).
- Thiazolidinediones activate nuclear receptors which work on the muscles to increase glucose uptake, they are going to act on the liver in order to decrease gluconeogenesis (and glycogen breakdown), they act on the beta cells of the pancreas to help increase insulin sensitivity, they aid in pulling in glucose (to lower blood sugar), and in addition they regulate fatty acid metabolism (to decrease ketone bodies in circulation).
- Metformin is going to stimulate the uptake of glucose in muscles (stimulates insulin response/sensitivity), as well as work to decrease the glucagon response pathways (decrease in glycogen breakdown and gluconeogenesis.
- Insulin activates the insulin receptor to decrease blood sugar (increases glucose uptake by stimulating more GLUT transporters at the cell membrane and more transcription of GLUT transporters), decreases lipolysis, as well as acting to decrease neurotransmitter dysfunction.
= Amylin (α-glucosidase inhibitor) works to inhibit glucagon secretion (alpha cells of pancreas) as well as helping to prevent the intestines from uptaking glucose.
Explain the pros/cons behind insulin use.
Pros: universally effective, never loses efficacy, and it has the ability to decrease cardiovascular risk
Cons: development of hypoglycemia, weight gain, cell division issues that can cause cancer. Requires training for injections
Explain the mechanism as well as the advantages/disadvantages between Metformin and Thiazolidinediones.
Metformin: activates the AMPK pathway and leads to a decrease in liver gluconeogenesis and glycogen breakdown. Advantages to this medicine is that there is extensive research behind it, it wont cause hypoglycemia, it will keep your weigth neutral, and can help decrease cardiovascular disease. Disadvantages to this is that it can cause certain deficiencies, and some medicines cannot mix with metformin (contraindications).
Thiazolidinediones activate PPARγ, increase insulin sensitivity, do not lead to hypoglycemia, have great durability, decrease circulating triglycerides, increases good cholesterol, as well as decreases cardiovascular disease (for pioglitazone). However, these can lead to weight gain, edema/heart failure, bone fractures, can lead to myocardial infarction (for rosiglitazone) and can lead to bladder cancer (pioglitazone).
