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233 2nd midterm > Type 1 Diabetes > Flashcards

Type 1 Diabetes Flashcards

1
Q

What happens in Type 1 Diabetes

what is needed to sustain life?

A

Selective beta-cell destruction (primarily thought to
be autoimmune-mediated) that results in severe or
absolute insulin deficiency

insulin therapy is vital

10-15% diabetics will maintain enough B cells and don’t require insulin

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2
Q

Most target goals with therapies for diabetes
are to achieve __________

why is this goal important?
what is it not effective for?

A

glycated hemoglobin levels ≤7%

  • Glycated hemoglobin = long term blood sugar control marker
  • (Hemoglobin 3-4 month lifespan)
  • Effective control of blood glucose in patients with
    diabetes reduces risk for microvascular complications
    ▪ Neuropathy
    ▪ Nephropathy
    ▪ Retinopathy

Will not prevent macrovascular disease which is a major killer

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3
Q

what is the normal physiologic patterns for insulin release?

A
  • there is a basal (continuous) release of insulin
  • spikes after meals where there is an increase in plasma glucose
  • beta cells will secrete insulin in response to the spike
    (intermittent bolus release)
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4
Q

what happens if you don’t take insulin? (2)

A

• Hyperglycemia
- doesn’t kill diabetic
• Diabetic ketoacidosis
– Fatal metabolic complication of uncontrolled
diabetes mellitus
– Leading cause of mortality in children and young
adults with type 1 diabetes
- can feel confusion, urination, fruity breath, heavy slow breathing
- due to increase in acetone

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5
Q

describe the pathway where ketone bodies are made

A

During prolonged starvation/fasting there is low blood sugar and brain needs to use ketone bodies for feul
- body mobilizes fat from adipose tissue for energy goes to liver and turns into ketone bodies for use in brain

  • T1 diabetic ketone bodies acidic and can cause toxicity
  • insulin is needed to shut off ketogenesis
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6
Q

basic structure of insulin?

A
  • protein
  • Proinsulin: insulin + C peptide
  • C peptide is hydrolyzed and cleaved off - no known bio activity
  • Insulin - hypoglycemic activity
  • B chain last 3 aa 28-30 are very important for insulin to form dimers
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7
Q

where is endogenous insulin stored?

which organs are responsible for removing insulin and what ratio? (2)

A

• Stored within granules in β-cells of pancreas
• Half-life of circulating insulin is 3-5 minutes
• Two organs are responsible for removing
insulin from the circulation
– Liver (~60%)
– Kidney (35-40%)

ratio is reversed in diabetics

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8
Q

Insulin has a natural tendency to self-associate and form _________

what problems may occur with this? how to deal with this?

A

hexamers

  • Hexamers is the ideal formation
  • For storing in islet cells
  • Type I Diabetic - barrier to absorption
  • Hexamer too long to diffuse into capillaries

3 rates of absorption of injected insulin and diffuses into subq tissue

  • hexamers to dimers
  • Dimers into monomers

Take insulin 30 mins before eating so it’s already in the bloodstream

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9
Q

what are the sources of exogenous insulin?

what are the two types?

A

• Available as an OTC drug
• Usual solution strength is 100 units/mL
• Principal source is recombinant DNA (rDNA)
technology from human proinsulin gene, grow in vector
– Eli Lily uses E coli to make their human insulin (Humulin)
– Novo Nordisk uses yeast to make their human
insulin (NovoLog)
• Animal insulin (bovine & porcine) available
only through the special access program
- people may have adverse rxns to animal insulin

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10
Q

what is regular insulin?

duration of action?

A

– Recombinant DNA technology from the human
proinsulin gene (significantly reduced antigenicity)
– Short acting insulin (administer ~30 min before
having a meal)
– Clear solution

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11
Q

what is Neutral Protamine Hagedorn (NPH or N)?

A

– Produced by adding protamine to regular insulin
– Reduces the absorption rate from an injection site
resulting in an intermediate duration of action
– Highest variability of absorption (25-50%)
– Cloudy solution

  • Endogenous proteases in body eat protamine, leading to a slower release of insulin in body
  • used with regular insulin
  • Mimic basal release of insulin - search for a better one
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12
Q

Rapid Acting Formulations (mimic meal-time

insulin) (3)

A 
– Aspart (NovoRapid® - Novo Nordisk)
– Glulisine (Apidra® - Sanofi Aventis)
– Lispro (Humalog® - Lilly)
➢Duration of action ~4-5 hrs
➢Lowest variability of absorption (5%)

more costly

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13
Q

Long Acting Formulations (mimic basal insulin) (3)

A

– Glargine (Lantus® - Sanofi Aventis)
– Detemir (Levemir® - Novo Nordisk)
– Degludec (Tresiba® - Novo Nordisk – Approved
Sept 2015)

Once daily insulin
Preferred long acting insulin
NPH - variable in a patient and also variable for diff patients

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14
Q

How are rapid acting insulin analogues modified?

A

modify insulin analogues so it can’t form dimers so rapidly absorbed upon injection (monomers)

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15
Q

how is each rapid acting insulin analogue changed? (FYI not tested)

A

• Insulin Lispro
– B chain position 28 proline & 29 lysine are reversed
to mimic insulin-like growth factor 1 (which does
not associate into dimers)
• Insulin Aspart
– B chain position 28 proline is changed into aspartic
acid (interferes with dimer formation)
• Insulin Glulisine
– B chain position 29 lysine is changed into glutamic
acid and 3 asparagine is changed into lysine
(interferes with dimer formation)

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16
Q

How are long acting insulin analogues modified?

A
  • modify insulin so it is a hexamer and long acting
17
Q

what are unique properties of insulin glargine?

  1. what does added arginine do?
A

long acting insulin
2 arginine residues are added
– Two positive charges added to carboxyl terminus of B chain
– Isoelectric point shifts
– Molecules are less water soluble at the isoelectric point, therefore, glargine will precipitate out at physiologic pH so it is slowly absorbed
– This also means the pharmaceutical preparation for glargine is an acidic solution

When insulin glargine is injected into subcutaneous tissue, which is at physiologic pH, the acidic solution is neutralized. Microprecipitates of insulin glargine are formed, from which small amounts of insulin are released throughout a 24-hour period, resulting in a relatively stable level of insulin throughout the day

18
Q

what are unique properties of insulin glargine?

  1. what does glycine do?
A

Glycine molecule (A chain)
Asn on 21 becomes Glycine
– Asparagine is degraded in acidic solution
– Replacement produces a more stable molecule

19
Q

insulin glargine

what is the duration of action?

A

Long Duration of Action (once daily injection)
– Onset of action in 1-1.5 hrs, maximum activity can be
maintained for up to 24 hrs

20
Q

name 2 other long acting insulin analogues

how do they increase duration of action?

A

Insulin Detemir
– B chain Position 30 threonine is removed and
myristic acid is attached to the position 29 lysine

• Insulin Degludec
– B chain position 30 threonine is removed and
hexadecanedioic acid is attached to the position 29
lysine

Acylation of insulin (addition of a fatty acid) allows insulin to bind serum albumin in a reversible manner
– Creates a circulating depot/reservoir of insulin that
is slowly released into the blood
- Higher affinity for insulin to stay in fatty tissue

21
Q

Insulin Action/Pharmacology

what is the receptor type?
where does it act on?
what are the main actions/end goals?
what type of hormones is it and what does it mean?

A

• Free insulin binds to insulin receptors
– Intrinsic receptor tyrosine kinase activity
– Primarily the muscle, adipose tissue, and liver
– Promotes glucose uptake, glucose metabolism, and
energy storage in muscle
– Reduces endogenous glucose production by the liver
– Anabolic hormone
▪ Glycogen storage in liver
▪ Fat storage in adipose tissue
▪ Protein synthesis in muscle

22
Q

Insulin Action/Pharmacology

how does it act on muscle, adipose tissue, liver, heart?
what happens at the receptors?

A
  • Phosphorylates as phosphate groups to target proteins
  • External alpha subunit that insulin binds to it and causes conformational change that makes insulin receptor dimerize with another insulin receptor
  • Internal beta subunits have tyrosine kinase activity and become close in prox and phosphorylates each other and serve as platform to recruit molecules that recognize the phosphorylated subunits
  • Muscle, heart, adipose: promote glucose uptake, metabolism, energy storage in muscle
  • Glucose enters these tissues
  • Stimulates protein synthesis in muscle, must eat before insulin
23
Q

Insulin Action/Pharmacology

  1. How does it lead to glucose uptake
A

– Activation of Akt and translocation of GLUT4 to the plasma membrane (muscle, fat)
- Akt tells Glut4 which is stored in vesicles to release transporter to cell membrane to allow glucose entry to cell, glucose uptake

24
Q

Insulin Action/Pharmacology

  1. How does it lead to glycogen synthesis
A

– a lot of glycogen is stored as fuel source during fasting
- Inhibition of GSK3 prevents GSK3- mediated inhibition of GS
- Akt phosphorylates and inhibits GSK3
- GSK3 phosphorylates glycogen synthase (GS) to
prevent synthesis of glycogen/storage of
glycogen
- Akt prevents this phosphorylation
- Now GS is active and stores glucose as
glycogen

25
Q

Insulin Action/Pharmacology

  1. How does it lead to stopping gluconeogenesis?
A

– Inhibition of FoxO1 reduces the transcription of numerous genes of gluconeogenesis (liver)

  • Tells liver to stop making glucose - increases expression of genes used to make glucose from aa and lactate (during fasting) to make normal blood sugar levels
  • Akt phosphorylates Fox01 (transc factor) and kicks it out of nucleus - can no longer turn on transcription
  • Cannot make glucose
26
Q

Insulin Action/Pharmacology

  1. How does it lead to protein synthesis?
A

– Activation of mTOR modifies numerous signaling molecules that turn on protein synthesis (muscle
– mTOR which is a master regulator of protein synthesis to turn on synth

27
Q

Insulin Action/Pharmacology

  1. How does it shut of ketogenesis and reduce lipolysis? (2)
A

– Activation of Akt leads to increased phosphodiesterase 3B activity, which degrades cAMP,
and reduces lipolysis (adipose tissue)
- decreases mobilization of fat from tissue
– Reductions in lipolysis reduce circulating free fatty acid delivery to the liver, thereby reducing rates of ketone body production

– Insulin activates acetyl CoA carboxylase (ACC) in the liver, which produces malonyl CoA
• Inhibits fatty acid oxidation
• Promotes fatty acid biosynthesis
- In order to make ketone body, liver oxidizes fat to ketone body
- Reduces rate of oxidation of fat which DOES make it to the liver

– This collectively leads to an inhibition of ketogenesis

28
Q

AE of insulin

A

– Hypoglycemia (low blood sugar levels)

– Localized lipodystrophy is either a loss or
hypertrophy of fatty tissue at the site of injection
▪ More common with animal source insulin
- Rotate injection sites to minimize this site

– Insulin allergy is rare resulting from localized
histamine release
▪ Likely caused by non-insulin components of solution
- IgE is the main one that can cause allergy
- Too much IgG = resistance to insulin

– Insulin resistance is very rare, caused by
development of anti-insulin antibodies in circulation

– Weight gain due to it being an anabolic hormone

29
Q

Glucagon Action/Pharmacology

how does it affect hepatic glucose output?

A

Glucagon & Hepatic Glucose Output
– Glucagon activation of the glucagon receptor GPCR is linked to activation of Gs proteins and activation of AC, increasing cAMP levels & activating PKA
– Activates glycogen phosphorylase to mobilize liver glycogen stores for increases hepatic glucose output to maintain normoglycemia
• Glucagon pens (1 mg) can be injected intramuscularly or subcutaneously
– In hypoglycemic individuals that go unconscious, may restore consciousness within 15 min to allow sugar ingestion

  • diabetics should carry pen for emergency

233 2nd midterm (13 decks)

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