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in diabetes mellitus your body has

trouble moving glucose which is the type

of sugar from your blood into your cells

this leads to high levels of glucose in

your blood and not enough of it in your

cells and remember that your cells need

glucose as a source of energy so not

letting the glucose enter means that the

cells star for energy despite having

glucose right on their doorstep in

general the body controls how much

glucose is in the blood relative to how

much gets into the cells with two

hormones insulin and glucagon insulin is

used to reduce blood glucose levels and

glucagon is used to increase blood

glucose levels both of these hormones

are produced by clusters of cells in the

pancreas called islets of langerhans

insulin is secreted by beta cells in the

center of these islets and glucagon is

secreted by alpha cells in the periphery

of the islets insulin reduces the amount

of glucose in the blood by binding to

insulin receptors embedded in the cell

membrane of various insulin responsive

tissues like muscle cells in adipose

tissue when activated the insulin

receptors cause vesicles containing

glucose transporter that are inside the

cell to fuse with the cell membrane

allowing glucose to be transported into

the cell glucagon does exactly the

opposite it raises the blood glucose

levels by getting the liver to generate

new molecules of glucose from other

molecules and also break down glycogen

into glucose so that I can all get

dumped into the blood diabetes mellitus

is diagnosed when blood glucose levels

get too high and this is seen among 10

percent of the world population there

are two types of diabetes type 1 and

type 2 and the main difference between

them is the underlying mechanism that

causes the blood glucose levels to rise

about 10% of people with diabetes have

type 1 and the remaining 90% of people

with diabetes have type 2 let's start

with type 1 diabetes mellitus sometimes

just called type 1 diabetes in this

situation the body doesn't make enough

insulin the reason this happens is that

in type 1 diabetes there's a type 4

hypersensitivity response or a cell

mediated immune response where a

person's own T cells at

the pancreas as a quick review remember

that the immune system has T cells that

react to all sorts of antigens which are

usually small peptides polysaccharides

or lipids and that some of these

antigens are part of our own body cells

it doesn't make sense to allow T cells

that will attack our own cells to hang

around until there's this process to

eliminate them called self tolerance in

type 1 diabetes there's a genetic

abnormality that causes a loss of self

tolerance among T cells that

specifically target the beta cell

antigens losing self tolerance means

that these T cells are allowed to

recruit other immune cells and

coordinate an attack on these beta cells

losing beta cells means less insulin and

less insulin means that glucose piles up

in the blood because it can't enter the

body's cells one really important group

of genes involved in regulation of the

immune response is the human leukocyte

antigen system or HLA system even though

it's called a system it's basically this

group of genes on chromosome 6 that

encode the major histocompatibility

complex or MHC which is a protein that's

extremely important in helping the

immune system recognize foreign

molecules as well as maintaining self

tolerance MHC is like the serving

platter that antigens are presented to

the immune cells on interestingly people

with type 1 diabetes often have specific

HLA genes in common with each other one

called

HLA dr3 and another called HLA dr4 but

this is just a genetic clue right

because not everyone with HLA dr3 and

HLA dr4 develops diabetes in diabetes

mellitus type 1 destruction of beta

cells usually starts early in life but

sometimes up to 90% of the beta cells

are destroyed before symptoms crop up

for clinical symptoms of uncontrolled

diabetes that all sound similar our

polyphagia glycosuria polyuria and

polydipsia let's go through them one by

one even though there's a lot of glucose

in the blood it cannot get into the

cells which leaves cells starved for

energy so in response adipose tissue

starts breaking down fat called

lipolysis

and muscle tissue starts breaking down

proteins both of which results in weight

loss for someone with uncontrolled

diabetes this catabolic state leaves

people feeling hungry

also known as poly fascia Faiza means

eating and poly means a lot now with

high glucose levels that means that when

blood gets filtered through the kidneys

some of it starts to spill into the

urine called glycosuria glyco surfers to

glucose and urea the urine since glucose

is osmotically active water tends to

follow it resulting in an increase in

urination or polyuria poly again refers

to a lot and urea again refers to urine

finally because there's so much

urination people with uncontrolled

diabetes become dehydrated and thirsty

or polydipsia poly means a lot and dip

SIA means thirst even though people with

diabetes are not able to produce their

own insulin they can still respond to

insulin so treatment involves lifelong

insulin therapy to regulate their blood

glucose levels and basically enable

their cells to use glucose

one really serious complication with

type 1 diabetes is called diabetic

ketoacidosis or DKA to understand it

let's go back to the process of

lipolysis where fat is broken down into

free fatty acids after that happens the

liver turns the fatty acids into ketone

bodies like Osito acetic acid in beta

hydroxy butyrate acid a seed of acetic

acid is a keto acid because it has a

ketone group in a carboxylic acid group

beta hydroxy rhetoric acid on the other

hand even though it's still one of the

ketone bodies isn't technically a keto

acid since its ketone group has been

reduced to a hydroxyl group these ketone

bodies are important because they can be

used by cells for energy but they also

increase the acidity of the blood which

is why it's called ketoacidosis and the

blood becoming really acidic can have

major effects throughout the body

individuals can develop custom all

respiration which is a deep and labored

breathing as the body tries to move

carbon dioxide out of the blood in an

effort to reduce its acidity cells also

have a transporter that exchanges

hydrogen ions or protons for potassium

when the blood gets acidic it's by

definition loaded with protons that get

sent into cells while potassium gets

sent into the fluid outside cells

another thing to keep in mind is that in

addition to helping glucose enter cells

insulin stimulates the sodium potassium

ATPase --is which help potassium get

into the cells and so without insulin

more potassium stays in the fluid

outside cells both of these mechanisms

lead to increased potassium in the fluid

outside cells which quickly makes it

into the blood and causes hyperkalemia

the potassium is then excreted so over

time even though the blood potassium

levels remain high over all stores of

potassium in the body which include

potassium inside cells starts to run low

individuals will also have a high anion

gap which reflects a large difference in

the unmeasured negative and positive

ions in the serum largely due to the

build-up of ketoacids

diabetic ketoacidosis can happen even in

people who have already been diagnosed

with diabetes and currently have some

sort of insulin therapy

in states of stress like an infection

the body releases epinephrine which in

turn stimulates the release of glucagon

too much glucagon can tip the delicate

hormonal balance of glucagon and insulin

in favor of elevating blood sugars and

can lead to a cascade of events we just

described increased glucose in the blood

loss of glucose in the urine loss of

water dehydration and in parallel and

need for alternative energy generation

of ketone bodies and ketoacidosis

interestingly both ketone bodies break

down into acetone and escape as a gas by

getting breathed out the lungs which

gives us sweet fruity smell to a

person's breath in general though that's

the only sweet thing about this illness

which also causes nausea vomiting and if

severe mental status changes and acute

cerebral edema

treatment of a DKA episode involves

giving plenty of fluids which helps with

dehydration insulin which helps lower

blood glucose levels and replacement of

electrolytes like potassium all of which

help to reverse the acidosis now let's

switch gears and talk about type 2

diabetes which is where the body makes

insulin but the tissues don't respond as

well to it the exact reason why cells

don't respond isn't fully understood

essentially the body's providing the

normal amount of insulin but the cells

don't move their glucose transporters to

their membrane in response which

remember is needed for the glucose to

get into the cells these cells therefore

have insulin resistance some risk

factors for insulin resistance are

obesity lack of exercise and

hypertension the exact mechanisms are

still being explored for example in

excess of adipose tissue or fat is

thought to cause the release of free

fatty acids in so-called edible kinds

which are signaling molecules that can

cause inflammation which seems related

to insulin resistance

however many people that are obese are

not diabetic so genetic factors probably

play a major role as well we see this

when we look at twin studies as well

we're having a twin with type-2 diabetes

increases the risk of developing type 2

diabetes completely independently of

other environmental risk factors in type

2 diabetes since tissues don't respond

as well to normal levels of insulin the

body ends up producing more insulin in

order to get the same effect and move

glucose out of the blood

they do this through beta cell

hyperplasia an increased number of beta

cells and beta cell hypertrophy where

they actually grow in size all in this

attempt to pump out more insulin this

works for a while and by keeping insulin

levels higher than normal blood glucose

levels can be kept normal called normal

glycemia now along with insulin beta

cells also secrete islet amyloid

polypeptide or amylin so while beta

cells are cranking out insulin they also

secrete an increased amount of amylin

over time Emlyn builds up and aggregates

in the islets this beta cell

compensation though is not sustainable

and over time those maxed out beta cells

get exhausted and they become

dysfunctional and undergo hypo trophy

and get smaller as well as hypoplasia

and die off as beta cells are lost in

insulin levels decrease glucose levels

in the blood start to increase in

patients develop hyperglycemia which

leads to similar clinical signs that we

mentioned before like Paul aphasia

glycosuria polyuria polydipsia but

unlike type 1 diabetes there's generally

some circulating insulin in type 2

diabetes from the beta cells that are

trying to compensate for the insulin

resistance this means that the insulin

glucagon balances such that diabetic

ketoacidosis does not usually develop

having said that a complication called

hyperosmolar hyperglycemic state or HHS

is much more common in type 2 diabetes

than type 1 diabetes and it causes

increased plasma osmolarity due to

extreme dehydration and concentration of

the blood to help understand this

remember that glucose is a polar

molecule that cannot passively diffuse

across cell membranes which means that

it acts as a solute so when levels of

glucose are super high in the blood

meaning it's a hyperosmolar State water

starts to leave the body cells and enter

the blood vessels leaving the cells were

relatively dry in travailed rather than

plump and juicy blood vessels that are

full of water lead to increased

urination and total body dehydration and

this is a very serious situation because

the dehydration of the body's cells and

in particular the brain can cause a

number of symptoms including mental

status changes in HHS you can sometimes

see mild ketone emia and acidosis but

not to the extent that it's seen in DKA

and in DKA you can see some hyper

osmolarity so there's definitely overlap

between these two syndromes

besides type 1 and type 2 diabetes there

are also a couple other subtypes of

diabetes mellitus gestational diabetes

is when pregnant women have increased

blood glucose which is particularly

during the third trimester although

ultimately unknown the cause is thought

to be related to pregnancy hormones that

interfere with insulins action on

insulin receptors also sometimes people

can develop drug-induced diabetes which

is where medications have side effects

that tend to increase blood glucose

levels the mechanism for both of these

is thought to be related to insulin

resistance like type 2 diabetes rather

than an autoimmune destruction process

like in type 1 diabetes diagnosing type

1 or type 2 diabetes is done by getting

a sense for how much glucose is floating

around in the blood and has specific

standards that the World Health

Organization uses very commonly a

fasting glucose test is taken where the

person doesn't eat or drink except the

water that's okay for a total of eight

hours and then has their blood tested

for glucose levels levels of 100

milligrams per deciliter to 120

five milligrams per deciliter indicates

pre-diabetes and 126 milligrams per

deciliter or higher indicates diabetes a

non fasting a random glucose test can be

done at any time with 200 milligrams per

deciliter or higher being a red flag for

diabetes another test is called an oral

glucose tolerance test where person is

given glucose and then blood samples are

taken at time intervals to figure out

how well it's being cleared from the

blood the most important interval being

two hours later levels of 140 milligrams

per deciliter to 199 milligrams per

deciliter indicate pre-diabetes

and 200 or above indicates diabetes

another thing to know is that when blood

glucose levels get high the glucose can

also stick to proteins that are floating

around in the blood or in cells so that

brings us to another type of test that

can be done which is the hba1c test

which tests for the proportion of

hemoglobin in red blood cells that has

glucose stuck to it called glycated

hemoglobin hba1c levels of 5.7% 26.4%

indicate pre-diabetes

and 6.5 percent or higher indicates

diabetes this proportion of glycated

hemoglobin doesn't change day to day so

it gives a sense for whether the blood

glucose levels have been high over the

past two to three months finally we have

the c-peptide test which tests for

byproducts of insulin production if the

level of c-peptide is low or absent it

means the pancreas is no longer

producing enough insulin and the glucose

cannot enter the cells

for type one diabetes insulin is the

only treatment option for type 2

diabetes on the other hand lifestyle

changes like weight loss and exercise

along with a healthy diet and an oral

anti-diabetic medication like metformin

in several other classes can sometimes

be enough to reverse some of that

insulin resistance and keep blood sugar

levels in check however if oral

anti-diabetic medications fail type 2

diabetes can also be treated with

insulin something to bear in mind is

that insulin treatment comes with a risk

of hypoglycemia especially if insulin is

taken without a meal symptoms of

hypoglycemia can be mild like weakness

hunger and shaking but they can progress

to a loss of consciousness in seizures

in severe cases in mild cases drinking

juices or eating candy or sugar might be

enough to bring blood sugar up but in

severe cases intravenous glucose should

be given as soon as possible

the FDA has also recently approved

intranasal glucagon as a treatment for

severe hypoglycemia all right now over

time high glucose levels can cause

damage to tiny blood vessels while the

micro vasculature in arterioles a

process called hyaline

arteriolosclerosis is where the walls of

the arterioles develop hyaline deposits

which are deposits of proteins and these

make them hard and inflexible in

capillaries the basement membrane can

thicken and make it difficult for oxygen

to easily move from the capillary to the

tissues causing hypoxia

one of the most significant effects is

that diabetes increases the risk of

medium and large arterial wall damage

and subsequent atherosclerosis which can

lead to heart attacks and strokes which

are major causes of morbidity and

mortality for patients with diabetes in

the eyes diabetes can lead to

retinopathy and evidence of that can be

seen on a fundus copic exam that shows

cotton-wool spots or flare hemorrhages

and can eventually cause blindness in

the kidneys the a ferrant and efferent

arterioles as well as the glomerulus

itself can get damaged which can lead to

an F Radek syndrome that slowly

diminishes the kidneys ability to filter

blood over time and can ultimately lead

to dialysis diabetes can also affect the

function of nerves causing symptoms like

a decrease in sensation in the toes and

fingers sometimes called a stocking

glove distribution as well as causes the

autonomic nervous system to malfunction

and that system controls a number of

body functions

everything from sweating to passing gas

finally both the poor blood supply and

nerve damage can lead to ulcers

typically on the feet that don't heal

quickly and can get pretty severe and

need to be amputated these are some of

the complications of uncontrolled

diabetes which is why it's important to

diagnose and control diabetes through a

healthy lifestyle medications to reduce

insulin resistance and even insulin

therapy if beta cells have been

exhausted while type 1 diabetes cannot

be prevented type 2 diabetes can in fact

many people with diabetes can control

their blood sugar levels really

effectively and live a full and active

life without any of the complications

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