in this lecture we are going to cover
drugs used for diabetes so 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 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 stored glycogen into glucose which is then released into
the bloodstream so now let's switch gears and let's talk
about drugs used 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 Lispro insulin
Aspart and insulin Glulisine 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 analog that belongs to this group is regular insulin which is
considered as short-acting with peak effect as quick as 2 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 analogs with faster
absorption and more rapid action next we intermediate acting insulin preparation
that falls into this category is NPH insulin also known as Isophane insulin
unlike the rapid acting insulins NPH insulin has a little slower onset of
action it produces peak effect somewhere around 6 hour mark and lasts
about 18 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 Detemir with a peak effect between 6 and 8 hours and duration
of action of up to 24 hours next insulin Glargine which doesn't
produce peak effect due to its steady delivery of insulin for about 24 hours
and finally we have insulin Degludec 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 Detemir
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 neutral pH
which causes it to form precipitate in the subcutaneous tissue that slowly
releases insulin into the bloodstream lastly insulin Degludec was
designed to form long chains of hexamers in subcutaneous tissue that
serve as a depot 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 site of
repeated insulin injections now let's move away from the insulins and let's
talk about different type of injectable analog used in treatment of diabetes
that is synthetic amylin so first of all what is amylin
well pancreatic beta cells not only secrete insulin but also another peptide
hormone called amylin amylin's job is to delay gastric
emptying to suppress postprandial glucagon secretion and to promote satiety
the only amylin mimetic that's currently available on the market is Pramlintide one of the biggest benefits of Pramlintide is that it allows insulin
doses to be reduced however the risk of hypoglycemia is still there other common
side effects associated with Pramlintide are nausea and modest weight loss
now let's move on to the last group of injectable analogs that is incretin
mimetics so first off what are incretins well incretins 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 incretin
hormones are glucagon-like peptide-1 GLP-1 for short and glucose-dependent
insulinotropic 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 mimetics
that are resistant to degradation by DPP-4 enzyme example of agents that
belong to this class are Exenatide and Liraglutide in addition to stimulating
insulin secretion GLP-1 mimetics slow gastric emptying and promote 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 pancreatitis associated with the use of GLP-1
mimetics this is thought to be due to their proliferative effects on pancreas now let's switch gears and let's talk
about oral antidiabetic agents so first I would like to discuss a class of drugs
closely related to GLP-1 mimetics namely DPP-4 inhibitors so another way
to enhance the effects of incretin 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 that belong to
this class include Alogliptin Linagliptin Saxagliptin and Sitagliptin side effects of DPP-4 inhibitors are similar to those of GLP-1 mimetics
with the most commonly reported being nasopharyngitis and headache now let's
move on to another class of oral antidiabetic agents that is sulfonylureas 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 2 abbreviated as GLUT2 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 mediate fusion of
insulin containing vesicles with the membrane leading to insulin release so
now what sulfonylureas do is they bind to and inhibit the activity of ATP-sensitive potassium channels this just like incoming glucose triggers membrane
depolarization calcium influx and ultimately insulin secretion other
actions of sulfonylureas include increased sensitivity of beta cells to
glucose and reduced hepatic glucose production example of drugs that belong
to this class are Glimepiride Glyburide and Glipizide some of the common side
effects reported with sulfonylureas are hypoglycemia and weight gain lastly
because sulfonylureas 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
antidiabetic agents that is glinides so just like sulfonylureas
the glinides 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 glinides
a good choice for patients with primarily postprandial hyperglycemia
example of drugs that belong to this class are Nateglinide and Repaglinide 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 antidiabetic agents that is biguanides
so unfortunately the exact cellular mechanism of action of biguanides is not
entirely understood that being said the main blood glucose lowering activity
appears to be primarily through reduction of hepatic glucose production
additionally biguanides 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 antidiabetic agents that is thiazolidinediones thiazolidinediones work primarily 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 well as insulin signal transduction this
leads to effects such as increased insulin sensitivity in adipose tissue
skeletal muscle and liver as well as inhibition of hepatic glucose production
additionally thiazolidinediones 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 increase HDL levels this increase is especially pronounced
with the use of Pioglitazone in part because of its effects not only on PPAR-gamma but also on PPAR-alpha as you may recall from my video discussing drugs
for hyperlipidemia PPAR-alpha is the main target of
fibrates which promote the formation of HDL
precursors on the other hand thiazolidinediones may also increase LDL levels
however this increase appears to be limited only to larger less atherogenic 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
now let's move on to yet another class of oral antidiabetic agents that is
sodium-glucose cotransporter-2 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 cotransporter-2 leads to
increased urinary glucose excretion and thus reduced levels of blood glucose
furthermore this increase in glucose and sodium in urine generate mild
osmotic diuresis which may contribute to small reduction in blood pressure and
weight loss drugs that belong to this class include Canagliflozin and Dapagliflozin when it comes to side effects the most common ones are thirst
increased urination and increased risk of urinary tract and genital infections now
let's move on to the final class of oral antidiabetic agents that is
alpha-glucosidase inhibitors so first what is alpha-glucosidase well
alpha-glucosidase is an enzyme located in the intestinal brush border that is
responsible for breaking down carbohydrates into simple sugars such as
glucose so when alpha-glucosidase 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 Miglitol 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



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