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Egregious Eleven of Type 2 Diabetes

Mellitus

There are eleven known pathoph siologic defects that T pe 2

diabetes mellitus (T2DM) is characteri ed b . These eleven features

are often referred to as the egregious eleven .

P i ac - Te

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1. Pancreatic beta cell dysfunction

The beta cells in the pancreas are responsible for producing and

secreting insulin in response to sugar levels in the blood. Beta cell

d sfunction is a ke feature of t pe 2 diabetes mellitus, and it leads

to h pergl cemia b impairing the bod s abilit to produce and/or

release insulin. Insulin resistance is a major contributing factor to

beta cell d sfunction, and it occurs when the bod s cells become

resistant to the effects of insulin.

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Te d
T i ha ic Re e f Diabe e I i id

This resistance can be caused b a number of factors, including

obesit , genetics, and certain medications. When the bod s cells

are resistant to insulin, the cannot effectivel uptake glucose from

the bloodstream, which leads to elevated blood sugar levels. Over

time, this can damage the beta cells and cause them to d sfunction

(progressive beta cell death). In addition, when the beta cells are

not functioning properl , the cannot secrete enough insulin to

keep blood sugar levels under control, which further e acerbates the

problem.

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2. Loss of the incretin effect

The two main t pes of incretins are glucose-dependent

insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-

1). GIP is produced b K and L cells of the intestine. GIP and GLP-1

work together to regulate blood sugar levels after a meal. GIP

promotes insulin secretion, while GLP inhibits glucagon release.

Te d
G ie

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The incretin effect is a major contributor to normal glucose

metabolism. It is the enhancement of glucose-dependent insulin

secretion and suppression of glucagon secretion in response to an

oral glucose load. The incretin effect is mediated b the gut

hormone GLP-1. GLP-1 is secreted b L cells in the intestine in

response to food intake. It acts on pancreatic beta cells to

stimulate insulin secretion and on liver cells to suppress glucagon

secretion. GLP-1 also dela s gastric empt ing and reduces food

intake (earl satiet ). In t pe 2 diabetes, there is a loss of the

incretin effect, which leads to uncontrolled h pergl cemia. This loss

of the incretin effect is thought to be due to a combination of

factors, including a decrease in GLP-1 secretion and an increase in

GLP-1 degradation. The loss of the incretin effect contributes to the

progressive deterioration of gl cemic control in t pe 2 diabetes and

is a major therapeutic target for the treatment of this disease.

Te d
A a f he a a h id g a d

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3. Pancreatic alpha cell dysfunction

Pancreatic alpha cell d sfunction is a condition in which the cells

that produce glucagon (a hormone that regulates blood sugar

levels) do not function properl . This often leads to elevated levels

of glucose in the blood, which can lead to t pe 2 diabetes.

Hyperglucagonemia (high levels of glucagon in the blood) is a

common complication of pancreatic alpha cell d sfunction and is

thought to contribute to the development of t pe 2 diabetes.

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4. Adipose tissue dysfunction (insulin

resistance)

Adipose tissue d sfunction is a major contributing factor to the

development of t pe 2 diabetes. In lipol sis, trigl cerides are broken

down into free fatt acids and gl cerol, and free fatt acids are

subsequentl released into the blood. Furthermore, free fatt acids

are then taken up b the liver, where the are used for energ or

stored as fat. With adipose tissue d sfunction, lipol sis is impaired

and free fatt acids are not properl metaboli ed. This results in

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increased levels of free fatt acids in the blood, which leads to

insulin resistance and t pe 2 diabetes.

5. Muscle tissue dysfunction (insulin

resistance)

Muscle tissue d sfunction is a major contributor to the

development of insulin resistance and t pe 2 diabetes mellitus

(T2DM). In skeletal muscle, lipol sis is increased in the setting of

insulin resistance and T2DM, which results in elevated

concentrations of free fatt acids (FFA). The accumulation of FFA in

muscle cells leads to impaired glucose uptake through the insulin-

sensitive GLUT-4 transporter, contributing to peripheral insulin

resistance. In addition, FFA accumulation promotes lipoto icit and

o idative stress, further e acerbating muscle tissue d sfunction

and insulin resistance. Thus, targeting muscle tissue d sfunction

represents a promising therapeutic strateg for the treatment of

T2DM.

6. Liver dysfunction (insulin resistance)

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Hepatic d sfunction is a pathophysiologic defect that can lead to

t pe 2 diabetes as well. Under normal circumstances, the liver

regulates glucose levels b gluconeogenesis (the process of

s nthesi ing glucose from non-carboh drate sources) and

glycolysis (the breakdown of glucose to generate energ ).

However, in hepatic d sfunction, the liver is unable to properl

regulate these processes, leading to increased hepatic glucose

output and decreased insulin sensitivit . This can eventuall lead to

t pe 2 diabetes if left untreated. The most common cause of

hepatic d sfunction is fatt liver disease, which is often linked to

obesit and insulin resistance.

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7. Brain dysfunction

The brain normall regulates appetite b sending signals to the

bod that tell it when to feel hungr and when to feel full. However,

in people with t pe 2 diabetes, this process is disrupted, leading to

higher levels of hunger and cravings for foods that are high in

sugar and fat. This can lead to weight gain and eventuall to t pe 2

diabetes. Although the e act cause of this appetite d sregulation is

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not et known, it is thought to be due to a combination of genetic

and environmental factors.

8. Colon dysfunction (Gut dysbiosis)

The gut microbiome is a comple ecos stem of microbes that

resides in the human gastrointestinal tract. This microbiota pla s a

critical role in gut health and has been shown to be involved in the

pathoph siolog of various diseases, including t pe 2 diabetes.

Studies have shown that gut d sbiosis, or an imbalance in gut

microbial composition, is associated with t pe 2 diabetes. This gut

d sbiosis can lead to impaired gut barrier function and increased

inflammation, both of which are thought to contribute to the

development of t pe 2 diabetes. Additionall , gut d sbiosis has

been shown to alter glucose metabolism, b blunting the abilit of

the intestines to produce incretins. This leads to significant

impairment of the previousl described incretin effect .

9. Immune system dysfunction

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It is now clear that immune d sregulation and inflammation pla a

significant role in the pathogenesis of t pe 2 diabetes. For e ample,

chronic low-grade inflammation has been shown to contribute to

the development of insulin resistance, while pro-inflammator

c tokines have been linked to beta-cell d sfunction and death.

These findings suggest that targeting inflammation ma be a

promising therapeutic strateg for treating T2DM.

10. Low amylin levels

Am lin is a peptide hormone that is secreted b the pancreas

along with insulin. Am lin pla s several important roles in regulating

glucose metabolism, such as slowing gastric empt ing and

promoting satiet . In individuals with t pe 2 diabetes mellitus, am lin

levels are often low, which can lead to h pergl cemia

11. Kidney dysfunction

In t pe 2 diabetes, renal glucose handling is impaired, and there is

an increase in SGLT-2 activit and SGLT-1-mediated glucose

reabsorption.

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Choosing pharmacotherapy based on

pathophysiologic defects
Pa c defec Med ca

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L f e ce effec GLP-1 a a , D a GLP-1 a d GIP a a

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Ad e ed f c ( Me f
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L a e e GLP-1 a a , D a GLP-1 a d GIP a a

Pa de (a a a )

Kd e d f c SGLT-2 b

What are the egregious eleven of

diabetes mellitus?

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The egregious eleven refers to the 11 core pathoph siologic

defects of t pe 2 diabetes mellitus.

1. Pancreatic beta cell d sfunction

2. Loss of the incretin effect

3. Pancreatic alpha cell d sfunction

4. Adipose tissue d sfunction (insulin resistance)

5. Muscle tissue d sfunction (insulin resistance)

6. Liver d sfunction (insulin resistance)

7. Brain d sfunction

8. Colon d sfunction (Gut d sbiosis)

9. Immune s stem d sfunction

10. Low am lin levels

11. Kidne d sfunction

References

Schwart SS, Zangeneh F. Evidence-based practice use of quick-

release bromocriptine across the natural histor of t pe 2 diabetes

mellitus. Postgrad Med. 2016 Nov;128(8):828-838.

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