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Flashcards in Diabetes Mellitus Deck (69):

Diabetes Mellitus

A group of disorders of glucose homeostasis – a syndrome characterized by chronic hyperglycemia and other disturbances in carbohydrate and fat metabolism

*an alteration in carbohydrate and fat metabolism


Three processes that regulate glucose homeostasis

1. Gluconeogenesis: glucose production in the liver (and some in kidney)

2. Glycogenolysis: glucose storage (skeletal muscle, and liver)

3. Insulin-mediated glucose uptake by peripheral tissue (especially skeletal muscle and fat)


Glucose and the CNS

Brain can’t use fatty acids for energy, it must use glucose for energy
*This is why you need to maintain critical level of glucose in blood in order to supply brain with adequate supply of glucose

Hyperglycemia is particularly toxic to vascular tissue and neuronal tissue peripheral nerves



Glucose production, generated from amino acids and lactic acid

Two organs carry out gluconeogenesis: liver and kidney



Storage of glucose in the form of glycogen (a huge polysaccharide composed of glucoses stringed together) then the breakdown of glycogen to release glucose into the blood

*We break down stored glycogen in order to add glucose to the blood


Tissues involved in glycogenolysis

Skeletal muscle: has glycogen stores to supply glucose for its own purposes, including muscle contractions

Liver: storage here is solely to contribute to glucose in the bloodstream
*liver plays central role in glucose homeostasis


Insulin-mediated glucose uptake

Uptake of glucose by insulin sensitize tissue

Uptake by peripheral tissue (especially skeletal muscle and fat) and the liver


Liver and Insulin-mediated uptake (4)

1. When liver cells take up glucose it reduces glucose in the bloodstream

2. When liver cells are not taking up glucose it preserves glucose in the blood stream

3. Process of taking up or not taking up glucose is mediated by presence or absence of insulin

4. Cells that limit uptake of glucose – in the absence of uptake they undergo metabolic switch from consuming glucose for energy to consuming fatty acids for energy (unlike the brain which can only use glucose)


Absorptive State (8)

1. Priority is to decrease plasma glucose (prevent marked elevation)

2. Happens while we consume food and when glucose is absorbed into blood stream

3. As we absorb glucose the priority is to prevent a dramatic rise in blood glucose and we do that by allowing glucose to enter cells and converting into glycogen
*Storing and allowing to enter cells

4. The uptake of glucose is high/tissue uptake is high

5. Glycogen synthesis is TURNED ON

6. Fat synthesis is turned on (stored in form of glycogen)

7. Eating – absorbing amino acids and enter skeletal muscle and help produce intracellular proteins

8. Blood glucose is also going to enter liver and get converted into stored glycogen and to a certain extent stored fat


Post-absorptive state

"Fasting state"

1. The priority is to increase/maintain plasma glucose (prevent marked drop) for central nervous system function

2. This occurs an hour or two after eating

3. No longer an absorptive source of blood glucose

4. Priority = prevent drop in BG and to maintain for CNS function, so glucose becomes scarce

5. Uptake of glucose by cells is reduced and we are not taking up glucose (no uptake by liver, skeletal, or fat tissue)


Liver during post-absorptive state (3)

1. Stop taking up glucose, breaks down glycogen, and putting glucose into the blood

2. if that isn’t enough and you prolong fasting state you might get close to using up capacity for glycogen breakdown (glycogenolysis)
--Under those circumstances, your liver will take amino acids from circulation and convert to glucose and turn on gluconeogenesis

3. In order to maintain a healthy blood glucose, liver has to replace what your brain is taking out, because brain continues to take up glucose during fasting state


Adipose tissue during post-absorptive state

Adipose tissue starts breaking down stored fat and released free fatty acids → used for energy

*can use fatty acids for energy


Skeletal muscle during post-absorptive state

uses stored glycogen for energy


How to maintain a healthy blood glucose?

Liver must replenish the glucose that your brain is using up, particularly during the post-absorptive state

This is done by glycogenolysis and gluconeogenesis


Glucose physiology during absorptive state (4)

1. Decrease in glycogenolysis and gluconeogenesis

2. Increase in tissue permeability to glucose (especially skeletal and fat muscle) mediated by insulin
-insulin levels rise

3. Increase in glucose storage (glycogen synthesis)

4. Limit use of fat as primary energy source/increase fat storage (lipogenesis)


Glucose physiology during post-absorptive state (4)

1. Release of glucose from stores (glycogenolysis) increases

2. Making of new glucose (gluconeogenesis) increases

3. Limit glucose access only to tissue that needs it (brain)
-insulin levels drop

4. Use of fat as primary energy source (lipolysis)


How does glucose get in and out of the cell? (2)

Facilitated diffusion, meaning:

1. Passive transport - need a concentration gradient (greater outside than inside) to move in

2. Facilitated diffusion - need glucose transporter proteins to carry glucose into the cell


Glut-1 Transporter (4)

1. Found on all cells in the body

2. Allows for minimal baseline amount of glucose to enter cells in our body

3. Consequence: glucose can trickle into any cell in our body through GLUT-1 transporters no matter what state we are in
-Absorptive or non-absorptive

4. Glut-1 is one of the reason diabetic patients have such high glucose levels
(can't control how much glucose gets into the cells because they are always allowed via GLUT-1)


GLUT-1 Transporter Expression

Expression changes depending on conditions of blood glucose over time

1. Prolonged chronic hyperglycemia --> only way the cells can control this is to reduce expression of GLUT-1
**High glucose levels will cause a suppression in GLUT-1 expression; not dramatic but measurable

2. Prolonged fasting state --> Increased GLUT-1 expression to maximize uptake


GLUT-4 Transporter (2)

"insulin stimulated uptake of glucose"

1. found on cardiac muscle, skeletal muscle, adipose tissue, and in liver tissue

2. Not always found on plasma membrane; normally found inside the cell and only insert themselves into plasma membrane in response to an insulin stimulation


PI-3K Pathway (4 steps)

1st: insulin binds to insulin receptor on cardiac, skeletal, liver and adipose cells

2nd: stimulates GLUT-4 to migrate to plasma membrane and exocytose

3rd: GT4 gets inserted into plasma membrane and allows for entry of glucose (insulin mediated uptake of glucose)

4th: PI-3K signaling pathway stimulates cell reproduction and division, synthesis of lipids, proteins and glycogen


MAPK Pathway

Stimulates cell growth/proliferation by insulin binding to insulin receptors on cardiac, liver, adipose, skeletal cells


What do MAPK and PI-3K pathways do?

Since Insulin is released during absorptive state which means it represents a state where glucose is plenty and energy is abundant, so....
Insulin signals cells to not only take up glucose and store it but also stimulates growth in cell division because it is a perfect time to grow cell



Implications of insulin as a growth factor (3 risks)

Diabetes in pregnancy/ Gestational diabetes

Risks associated with DM in pregnancy:
1. Risk of hypergycemic mother and baby

2. Risk for large for gestational age baby

3. LGR baby --> risk for hypoxia, uterine demise, still birt


Islet Of Langerhans

organization of the endocrine pancreas; made up of alpha cells and beta cells

A) Alpha cells: produce glucagon

B) Beta cells: produce insulin


Regulation of glucose is done by...

Insulin and Glucagon, which are reciprocally regulated/released

*Both come from pancreas

Post-absorptive state: glucagon actions

Absorptive state: insulin actions


what triggers release of insulin? (2)

1. Rise of blood glucose
2. Drop of glucagon


what triggers release of glucagon? (2)

1. Drop in blood glucose
2. Drop in insulin


Effects of exercise on glucose

Physical activity --> triggers stress response and SNS --> production of cortisol and release of glucagon --> increased BS

*The rise of BS during exercise is managed well because glucose has the ability to enter insulin sensitive cells without GLUT-4 transporter


Effects of exercise with T1DM

When T1DM exercises, the need for insulin drops because there is an uptake of glucose after exercise

*Exercise promotes insulin-independent uptake of glucose


Cephalic phase (3)

1. The first 10 minutes of eating; rapid first phase of insulin release (up and down immediately)

2. Body anticipates food entering stomach (cues= smelling food, chewing, motility in stomach, etc)

3. Part of what cues this bolus in insulin that gets released is the anticipation of food


Second phase insulin release (3)

1. Actual change in blood glucose as glucose is absorbed
*Flat line of insulin release until there is a gradual decrease
*occurs in healthy individuals

2. The trigger of the second phase is an actual rise in blood glucose, not the anticipation of it

3. As you absorb a meal, BS increase and insulin increases proportionally as a response (healthy individuals)


Advantage of the two phases of insulin release (2)

1. Prevents consuming food from causing blood glucose to shoot up too high before it can come back down

2. Helps control the first phase and the peak in BS after consuming food


Type I DM (3)

1. Beta cell destruction, leads to absolute insulin deficiency

2. Immune-mediated and idiopathic

3. Absolute production and concentration of insulin is greatly reduced due to the destruction of beta cells


Type II DM (4)

1. Insulin resistance with relative insulin deficiency

2. Insulin is there but it has become resistant to a certain extent

3. Strongly influenced by genetic and environmental/lifestyle factors

4. The most powerful risk factor in type 2 diabetes is obesity - specifically a high abdominal adiposity (waist –to-hip ratio of greater than 1), and increased visceral adiposity


Genetic Defects of Beta cell function

Maturity-onset diabetes of the young (MODY), caused by mutations in several autosomal (sex independent) genes producing defects in insulin production

*There are varying genetic defects in beta cell function or insulin production is low to the point of non-functional
*MODY tends to present like a mild form of T1DM


Exocrine pancreatic defects (4)

1. Acute/Chronic pancreatitis, Pancreatectomy, Neoplasia, cystic fibrosis, etc.

2. Chronic pancreatitis
--Destroys the endocrine pancreas
--Slow destruction of pancreatic tissue and a loss of insulin and glucagon

3. Cystic fibrosis
--Inflammation in exocrine and causes damage to endocrine

4. RESULT: Lose ability to produce insulin and glucagon
--Manifest like T1DM***


Endocrinopathies (4)

1. Acromegaly, Cushing Syndrome, Hyperthyriodism, etc.

2. Causes an increased risk of hyperglycemia; increase in blood glucose

3. No dysfunction in insulin

4. Patient with one of these leading to hyperglycemia → Present similar to T2DM diabetic


Infections (3)

1. Cytomegalovirus, Coxsackie virus B, etc.

2. Certain infections when occurring in childhood are associated with a higher prevalence of T1DM that also presents in childhood

3. Some connection with children getting certain infections as a child and some proceeding to develop T1DM


Drugs and blood sugars (6)

1. Glucocorticoids,
2. Thyroid hormone,
3. α-interferon,
4. β-adrenergic agonists,
5. Protease inhibitors,
6. Thiazides, etc.

*These elevate and cause hyperglycemia


Genetic syndromes associated with diabetes

1. Down syndrome,
2. Turner syndrome,
3. Kleinfelter syndrome, etc.
*Chromosomal syndromes

*Higher prevalence in patients with these disorders of diabetes

*On same chromosome affected by conditions and increase risk for diabetes


Gestational Diabetes

Temporary diabetic state that comes on during pregnancy and presents after 20 weeks
**Caused by interaction of placental hormones with this blood glucose system and it gets resolved within a few days after birth when placenta gets delivered

CURE = delivery of placenta


Impaired glucose tolerance

A type of pre-diabetes

Abnormal pre-diabetic range for a diabetes screening test called oral glucose tolerance test


Impaired fasting glucose

A type of pre-diabetes

At least two occasions you have had a fasting glucose value that is above the normal limits but below criteria for diabetes
*Range = 100-126 with a blood glucose of greater than 126 being diagnostic for diabetes


HbA screening (3 with levels)

1. Looks at % of glycosolated hemoglobin
--Glucose can bidn to Hgb, and the higher the blood glucose there is, the more that will attach to Hgb

2. When hemoglobin is found with gluocse = HbA1C level
*Normal = 6,4%

3. Gives you a sense of glucose over a long period time (vs. fasting levels which are a snapshot)


Advantage of glucose challenge test

Allows you to diagnose very early and preclinical stages of diabetes; mimics the dynamics of insulin release and glucose changes over time in response to fod


Disadvantage of OGCT

You don't want to give someone 75mg glucose if you suspect diabetes


Types of T1DM

1. Immune type 1 (has beta antibodies and T cells reactive to pancreatic cells)

2. Idiopathic type 1 (clinical presentation is identical to T1DM but there are no indications of autoimmunity)


T1DM Characteristics (3)

1. Absolute insulin deficiency

2. Exceedingly high levels of glucagon (although some T1DM cannot produce glucagon)

3. After a few years of high glucagon levels, their alpha cells burn out and they no longer produce glucagon


Pathogenesis of T1DM (2)

1. Most commonly develops in childhood and becomes manifest at puberty
**Rise in sex hormones that accelerates things to presentation

2. The clinical onset is abrupt but the autoimmune attack is chronic and usually starts many years before (classic manifestations occur at >90% beta-cell destruction)
*Autoimmune beta cell attack is chronic and slow
*90% destruction of beta cells T1 is going to present abruptly
*Clinical onset = abrupt


Mechanisms for Beta-cell destruction

T cell-mediated immune attack against poorly defined beta-cell antigens

1. Cytokine-induced beta-cell damage (IFN-γ, TNF-α, IL-1 induced apoptosis) as a result of inflammation in immune attack

2. Autoantibodies against islet cells or insulin (detected in 70-80% of patients), usually accompanied by autoantibodies against beta-cell antigens


T1DM Genetic Susceptibility

1. Almost always genetic component to development of T1DM
2. Underlying autoimmunity

3. T1DM at birth - you have underlying autoimmunity and have it triggered to immune system attacks beta cells


MHC and T1DM

Part of genetic susceptibility

A. The MHC locus – presence of certain MHC II alleles (affects T cell antigen presentation)

B. Non-MHC genes – tandem repeat polymorphs of insulin gene (affects negative selection of insulin-reactive T cells)


T1DM Environmental Factors

Certain viral infections (mumps, rubella, etc.) are thought to increase the likelihood of autoimmune triggering
*Associated with precipitating triggering of autoimmunity
*Of children that have developed T1DM there is a higher than normal rate of infections that proceed it
*Age 3, 5, 10, 20, 40
-more likely to be triggered in childhood


T2DM and fat carrying (4)

How you carry increased body fat:

1. People who carry fat in middle of body – abdominal = highest rate

2. Pear shape → low waist to hip ratio → even if you have higher BMI but on butt and thighs is not associated with higher risk of diabetes

3. Central adiposity is the WORST* close proximity to the liver and seems to interfere with liver ability to regulate glucose more than fat anywhere else

4. Males: under muscle fat is worse than subcutaneous fat


Metabolic defects with T2DM (2)

1. Decreased sensitivity to insulin by peripheral tissue (insulin resistance)
-Takes more insulin than before to elicit same control of blood glucose
-Beta cells are pressured to produce more insulin to overcome resistance and eventually they start to burn out and see beta cell destruction
-Someone can be insulin resistant for years with no evidence of diabetes but pancreas constantly gets signal to produce more insulin = chronic injury

2. Beta-cell dysfunction manifested as inadequate insulin secretion relative to insulin resistance and hyperglycemia

*In most cases, insulin resistance is the primary event and beta-cel dysfunction is the secondary event


Abnormalities of insulin signaling pathway with T2DM (5)

1. Down-regulation of insulin receptors

2. Decreased insulin receptor-initiated kinase activity

3. Reduced levels of insulin receptor signaling intermediates (PI-33K and MAPK)

4. Impaired docking and fusion of GLUT4-containing vesicles with the plasma membrane

5. Pancreas' ability to produce insulin will decline


T2DM Beta Cell Dysfunction

The beta-cell dysfunction in Type-2 DM reflects the inability of these cells to adapt themselves to the long-term demands of peripheral insulin resistance (IR)

*B cell dysfunction is direct result of insulin resistance
*Means for a period of time the person may actually be overproducing insulin in order to compensate for resistance
*Hyperinsulin state to maintain normal glucose values
*Increased functional demand = injury to beta cells
*Initially, insulin secretion is higher at every level of plasma glucose with IR, this


Early B Cell Failure Manaifestations (3)

1. Loss of normal pulsatile/oscillating pattern of insulin secretion

2. Loss of the “rapid phase” of insulin secretion triggered by elevation of plasma glucose.

3. Eventually secretory defects affect all phases of insulin release, even though some basal secretion persists


Late B-cell failure manifestations (4)

1. Decreased beta-cell mass

2. Islet cell degeneration

3. Amyloid islet deposition

4. Fibrosis and scaring of islet cells (Deposition of scar tissue)


Pre-diabetic phase (3)

1. Insulin secretion is faltering

2. Somewhat controlling BS but not perfectly

3. As you get to T2DM range you start to see T2DM because of the rise in insulin resistance but mainly because of impaired secretion of insulin


Obesity and insulin resistance (4)

1. When adipose cells are forced to store greater than normal amount of fat they represent injured cells

2. Obese adipose cells are hypertrophied cells that are injured and cell injury triggers inflammation and inflammation messes up everything including with interfering with cells ability to regulate body mass and energy balance

3. Obesity is associated with insulin resistance (regardless of presence of DM) especially with central adiposity

4. Prolonged caloric overload and a hypertrophied state causes derangement of the normal adipocyte endocrine function



acts on brain to suppress appetite

*Hormone released by adipose tissue, especially with healthy fat tissue

*Greater the adipose mass = the more adipose tissue = the more leptin is produced and effect is to suppress appetite


Adiponectin vs. Resistin

Two chemical mediators that directly affect sensitivity of cells to insulin

A) Adiponectin: increases sensitivity to insulin

B) Resistin: decreases sensitivity of cells to insulin


Adiponectin release

Supposed to be in response to long term changes in energy stores
*Warm months of year where we can hunt and gather and then we go into winter where we are not hunting, so we are eating stored food

During warm weathers: we produce adiponectin and promote storage of glucose as fat stores


Resistin release

During "lean times," where we break down stored fat and use it as energy and save glucose for the brain


Obese adipose tissue (5)

1. Hypertrophied, injured and inflamed does not work this way

2. Inflamed adipose has difficulty releasing lectin so you have disconnect between adipose tissue and suppression of hunger

3. Impairment of ability to produce adiponectin

4. Overproducing resistin

5. Strong hypothesis with some support to connect obesity and prevalence of T2DM


How free fatty acids lead to insulin resistance

1st: Obesity causes elevated circulating free fatty acids

2nd: FFAs directly contribute to insulin resistance

*Chronic inflammation causes increased lipolysis in adipose tissue which elevates circulating FFAs


How obesity leads to insulin resistance (5 steps)

1st: Hypertrophy of adipocytes; if you force body to store more fat, it will cause cells to hypertrophy

2nd: Reaches a point where it can no longer hypertrophy, and that stimulates production of new fat cells

3rd: Once you produce new fat cells, you can't lose them even if you lose weight

Hypertrophy adipocytes --> injury --> inflammation --> inflammatory cytokines --> macrophages

4th: The macrophages that responded to hypertrophy of adipocytes cause chronic inflammation

5th: Chronic inflammation causes insulin resistance and disruption of insulin signaling pathway in fat, skeletal muscle, and liver cells (especially TNF-alpha)

*Being obese leads to chronic inflammation which results in insulin resistance