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