Pharmacology Of Diabetes
Let’s get right into it:
Diabetes mellitus is a chronic disorder characterized by high levels of blood glucose that result from either inadequate insulin production or resistance of the body’s cells to the action of insulin. Now, the two most commonly encountered types of diabetes are:
Type 1 Diabetes
Type 1 in which insulin producing cells are destroyed thus eliminating insulin production and the second is type 2 in which there is insulin resistance and gradual insulin deficiency but first things first what is insulin and how does it work well it all starts with the food that we eat which for the most part gets broken down by our digestive system into glucose following a meal when the blood glucose levels rise beta cells of the pancreas islets start secreting insulin insulin is a peptide hormone that binds to the insulin receptor and stimulates glucose uptake by our cells now under the influence of insulin liver and skeletal muscle store absorbed glucose in form of glycogen many other cells quickly break down absorbed glucose to make ATP a molecule which provides immediately available energy so in summary you can think of insulin as a key for entrance of glucose into cells which either use it immediately for energy or store it in order to meet future demand.
So now what happens when blood glucose levels fall too low?
Well if that’s the case alpha cells of the pancreatic islets release a different peptide hormone that is glucagon glucagon simply has the opposite effect of insulin so for example when it acts on the liver it causes breakdown of sort glycogen into glucose which is then released into the bloodstream so now let’s switch gears and let’s talk about drugs use for diabetes the first group of agents I would like to discuss is insulin and it’s analogs so human insulin can be reproduced by recombinant DNA technology using bacteria or yeast the amino acid sequence of human insulin can also be altered to produce insulin analogs with different onset and duration of action now because insulin is a polypeptide it is susceptible to degradation in the gastrointestinal tract therefore in order to be effective it’s typically administered by subcutaneous injection insulin preparations are generally divided into three major categories based on how quickly and how long they work so first we have rapid and short acting insulins preparations that fall into this category are insulin list pro insulin aspart and insulin glue lysine which are considered as rapid-acting producing peak effect in as quickly as 30 minutes and duration of action of up to 5 hours another analogue that belongs to this group is regular insulin which is considered as short acting with peak effect as quick as two hours and duration of action usually less than 8 hours.
Now you may wonder what gives these analogs the ability to act quickly well here’s the thing insulin molecules naturally like to stick together forming so-called hexamers that is six insulin molecules bound together these hexamers are too large to cross from the subcutaneous tissue into the bloodstream therefore they must first separate into single insulin molecules before absorption can occur so now what the clever scientists did is they altered amino acid sequence of insulin molecules to make them less likely to aggregate which resulted in animals with faster absorption and more rapid action next we intermediate acting insulin preparation that falls into this category is NPH insulin also known as I so feign insulin unlike the rapid acting insulins NPH insulin has a little slower onset of action it produces peak effects somewhere around six hour mark and lasts about eighteen hours these longer lasting effects are accomplished simply by addition of zinc and protamine to regular insulin which results in a complex that is less soluble. The final outcome is delayed absorption and thus, longer duration of action finally we have long-acting insulins with slow onset of action preparations that fall into this category are the following insulin Delamere with a peak effect between six and eight hours and duration of action of up to 24 hours next in Swannack large in which doesn’t produce peak effect due to its steady delivery of insulin for about 24 hours and finally we have insulin de gloried which also doesn’t produce peak effect and lasts beyond 24 hours and again all these long-lasting effects are the result of modifications to the insulin molecule in case of insulin dimer fatty acid side chain was added to the insulin molecule which allows it to bind to albumin and thus slow down its release into the bloodstream.
Insulin glargine on the other hand was modified to have low solubility at mutual pH which causes it to form precipitate in the subcutaneous tissue that slowly releases insulin into the bloodstream lastly insulin the glue that was designed to form long chains of hexamers in subcutaneous tissue doctor say depo from which insulin is continuously and slowly released now when it comes to side effects not surprisingly hypoglycemia or low blood glucose is the most common one associated with the use of insulin another adverse effect is lipodystrophy which can develop at the side of repeated insulin injections now let’s move away from the insulin sand talk about different type of injectable analog used in treatment of diabetes that is synthetic emmalin so first of all what is emmalin well pancreatic beta cells not only secrete insulin but also another peptide hormone called emmalin. Emmalin’s job is to delay gastric emptying to suppress postprandial glucose secretion and to promote satiety yummy emmalin mimetic that’s currently available on the market is prom lean type one of the biggest benefits of Crumlin type is that it allows insulin doses to be reduced however the risk of hypoglycemia is still there other common side effects associated with Kremmling type are nausea and modest weight loss now let’s move on to the last group of injectable analogues that is incredibly Mattox so first of water in credits what increments are a group of metabolic hormones that are secreted from the gut in response to food ingestion and their job is to stimulate pancreas to produce more insulin the two primary in credit hormones are glucagon-like peptide one glp-1 for short and glucose dependent insulin or tropic polypeptide GIP for short. So in theory increasing concentrations of these hormones would benefit patients with diabetes however as it turns out their actions are actually quite limited as a result of rapid inactivation by the enzyme dipeptidyl peptidase-4 dpp-4 for short to solve this problem scientists were able to develop glp-1 pneumatics that are resistant to degradation by dpp-4 enzyme example of agents that belong to this class are exotic and liraglutide in addition to stimulating insulin secretion GOP one pneumatic slow gastric emptying and promotes satiety as a result patients using these agents often experience weight loss.
Some common side effects also include GI problems such as nausea vomiting diarrhea and constipation lastly there have been some reports suggesting increased risk of pancreatic is associated with the use of glp-1 pneumatics this is thought to be due to their proliferative effects on pancreas now let’s switch gears and let’s talk about oral anti-diabetic agents so first I would like to discuss a class of drugs closely related to glp-1 pneumatics namely dpp-4 inhibitors so another way to enhance the effects of in credit hormones is to simply inhibit dpp-4 enzyme which is responsible for the inactivation of glp-1 and GIP by promoting the activity of glp-1 and GIP hormones we increase insulin secretion decrease gastric emptying and reduce glucagon release drugs are belonged to this class include alum Lipton linagliptin saxagliptin and sittig Lipton side effects of dpp-4 inhibitors are similar to those of GOP one memetics with the most commonly reported being nasopharyngitis and headache now let’s move on to another class of all anti-diabetic agents that is to follow ureas so in order to understand how sulfonylureas work first we need to review the mechanism of glucose dependent insulin secretion from pancreatic beta-cells so available glucose enters beta cell through glucose transporter – abbreviated as G LUT – once inside the cell glucose gets metabolized to create a bunch of ATP next the rising levels of ATP lead to inhibition of ATP sensitive potassium channels thus blocking the inflow of potassium this in turn leads to depolarization of the cell’s membrane which triggers activation of voltage-gated calcium channels and then influx of calcium finally increased levels of calcium mediated fusion of insulin containing vesicles with the membrane leading to insulin release.
so now, what ureas do is they bind to and inhibit the activity of ATP sensitive potassium channels this just like in common glucose triggers membrane depolarization calcium influx and ultimately insulin secretion other actions of sulfonylureas include increased sensitivity of beta cells to glucose and reduce hepatic glucose production example of drugs that belong to this class are climatic glyburide and glipizide some of the common side effects reported with sulfonylureas are hypoglycemia and weight gain lastly because so finally Ria’s are highly protein bound and most are extensively metabolized in the liver by cytochrome p450 enzymes they tend to interact with wide variety of other drugs now let’s move on to another class of oral anti-diabetic agents that is Glen Knights so just like so Connelly Ria’s the Golan Heights also stimulate insulin secretion from pancreatic beta cells however they accomplish that by binding to ATP sensitive potassium channels at a different site and with different kinetics than sulfonylureas as a result they have a more rapid onset and shorter duration of action this makes Glen it’s a good choice for patients with primarily postprandial hyperglycemia. example of drugs that belong to this class are in a tag line ID and rep tagging a common side effects include hypoglycemia and weight gain however the risk appears to be lower in comparison to sulfonylureas now let’s move on to another class of oral anti-diabetic agents that is biguanide.
So unfortunately the exact cellular mechanism of action of biguanide is not entirely understood that being said the main blood glucose lowering activity appears to be primarily through reduction of hepatic glucose production additionally biguanide appear to slow intestinal absorption of glucose and increase insulin sensitivity which enhances peripheral glucose uptake the only biguanide that’s currently available on the market is metformin most common side effects of metformin are limited to GI tract and include nausea vomiting diarrhea and loss of appetite which may lead to weight loss lastly because metformin decreases hepatic uptake of lactate it may increase risk of lactic acidosis particularly in patients with organ dysfunction such as congestive heart failure or renal impairment
now let’s move on to another class of oral anti-diabetic agents that work commonly by selectively activating nuclear receptor called peroxisome proliferator activated receptor gamma PPAR gamma for short when activated this receptor binds to DNA triggering expression and repression of specific genes encoding proteins that regulate glucose and lipid metabolism as was insulin signal transduction this leads to effects such as increased insulin sensitivity in adipose tissue skeletal muscle and liver also was inhibition of hepatic glucose production additionally ties volume and ions promote fatty acids uptake and utilization in adipocytes this decrease in fatty acid concentrations in turn leads to increased uptake and utilization of glucose example of drugs that belong to this class are pioglitazone and rosiglitazone now when it comes to side effects in addition to lowering blood glucose levels thiazolidinediones increased HDL levels this increase is especially pronounced with the use of pioglitazone in part because of its effect not only on PPAR gamma but also on PPAR alpha as you may recall from my video discussing drugs for hyperlipidemia P P air alpha is the main target of fibrates which promote the formation of HDL precursors on the other hand thyroid and ions may also increase LDL levels however this increase appears to be limited only to larger lesser thoreau genic LDL particles as for the other side effects the use of thiazolidinediones has been associated with weight gain and fluid retention leading to peripheral edema few cases of hepatotoxicity have also been reported.
Sodium glucose Scott sporter two inhibitors
Now, let’s move on to yet another class of oral anti-diabetic agents that is sodium glucose Scott sporter two inhibitors so these agents simply inhibit glucose transporter located in the proximal convoluted tubules of the kidneys that is responsible for about 90% of glucose reabsorption inhibition of sodium glucose co-transporter 2 leads to increased urinary glucose excretion and thus reduce levels of blood glucose furthermore this increase in glucose and sodium in the urine generate models modak diuresis which may contribute to small reduction in blood pressure and weight loss drugs that belong to this class include canagliflozin and the pagla flossin when it comes to side effects the most common ones are thirst increase urination and increased risk of urinary tract and general infections now let’s move on to the final class of oral anti-diabetic agents that is alpha-glucosidase inhibitors so first what is alpha-glucosidase well alpha-glucosidase is an enzyme located in an intestinal brush border that is responsible for breaking down carbohydrates into simple sugars such as glucose so when other glucose that is inhibitor blocks this enzyme the absorption of glucose is delayed resulting in lower postprandial glucose levels drugs that belong to this class include acarbose and Miguelito now one of the biggest disadvantages of these agents is their significant gastrointestinal side effects which include abdominal cramps bloating flatulence and diarrhea and with that I wanted to thank you for watching I hope you enjoyed this video and as always stay tuned for more.