Diabetes Flashcards
Cardinal Signs of Diabetes
Polydipsia (extreme thirst)
Polyuria (high volumes of urine production)
Polyphagia ( Lack of weight- gain)
Diagnosis of Diabetes
Fasting blood glucose >= 126 mg/dl
A1C >= 6.5%
Random glucose >= 200mg/dl
2 hr postprandial glucose >= 200mg/dl during an OGTT
Type 1 Diabetes
Glucose intolerance
- No functional insulin-secretion: near to complete loss of pancreatic cells
- These patients cannot secrete insulin during high levels of blood glucose so they have to take exogenous insulin (medications)
- Early onset (mean = 12)
- Patients at risk of metabolic acidosis
Auto-antigens associated with Type 1 diabetes
Insulin, islet antigen 2, Phogin, Zinc transporter, Glutamic acid decarboxylase, Voltage gated Ca, Vesicle associated membrane protein-2
Consequences of lack of insulin
Hyperglycemia -
1. Decreased glucose uptake in cells where glucose uptake in insulin dependent patients
2. decreases glycogen synthesis
3. Increased conversion of amino acids to glucose (gluconeogenesis)
Glucosuria -
1. due to high blood pressure
Hyperlipidemia -
1. Increased fatty acid mobilization from fat cells
2. increased fatty acid oxidation - Ketoacidosis
Unhibited glucagon -
1.Increased glucagon levels in the presence of increased blood glucose levels
Complications due to hyperglycemia
- Cardiovascular- Hyperglycemia can cause damage to small and large blood vessels which lead to compromised blood flow
- Neuropathy - accumulation of glucose in nerves that then gets reduced to aldose reductase through the poyol pathway so the ability of the nerves to prevent oxidative damage is compromized
- Nephropathy - Can compromise kidney functions due to renal vascular changes and changes in the glomerular basement membrane
- Ocular - Cataracts, retinal microaneurysms and hemorrhage
- Increased susceptibility to infections
Goal of insulin therapy and monitoring
Goal : Keeping average blood glucose levels below 150 mg/dL
Goal therapy levels
- Fasting : 70-110 mg/dL
- Pre meal : 80-130 mg/dL
- Post meal : <180 mg/dL
HbA1C: <7%
IDEAL goals of therapy
- Fasting : 70-90 mg/dL
- Pre meal : 70 - 105 mg/dL
- Post meal : <120-160
HbA1C : <6%
Is tight glycemic control worth the risk of hypoglycemia
Yes,
running the risk of hyperglycemia is worth it due to the life threatining factors associated with diabetes and high levels of A1C
Non-obese type 2 diabetes (non-insulin dependent)
Incidence in diabetic population: 10%
Age of Onset: Often under 25 ( also known as MODY)
Family history: Yes
Insulin secretion in response to glucose challenge: Low
- Mutations in specific beta cell proteins
Obese Type 2 diabetes (non-insulin dependent)
Incidence in diabetic population: 80%
Age of Onset: Usually over 35
Family history: yes
Insulin secretion in response to glucose challenge: Due to the high body mass although their body produces regular levels of insulin its not enough for their body mass
how does hypergylcemia lead to covalent modification of proteins?
Oxidation products of glucose react irreversibly with proteins which form advanced glycation end products which leads to loss of normal protein functions and can cause acceleration of aging (leads to many long term complications of diabetes
Receptor of advanced glycation endproducts (RAGE)
peptides bind to CML and CEL to bind to RAGE and cause inflammation
Complications due to hyperglycemia
Neuropathy Mechanism
The Polyol Pathway is how nerves process glucose for storage. When high levels of glucose are present this pathway depletes NADPH. With low levels of NADPH the nerves cannot protect neurons from oxidative damage leading to neuropathic problems
Complications due to hyperglycemia
Protein Modification
- Hexosamine pathway - due to high levels of glucose we also see a high level of Fructose-6-P which is taken into the hexosamine pathway and made into glucosamine-6-P which can become UDP-GlcNAc and can become a side chain to proteins and alter their function
- Protein Kinase C pathway - Glyceraldehyde-3-P enters this pathway to bind to DAG which activates protein kinase C
The insulin receptor
Role of alpha subunit
to repress the catalytic activity of the beta subunit (cross-linked). This repression is relieved when insulin binds
The insulin receptor
Role of beta subunit
Autophosphorylation
Contains the tyrosine kinase catalytic domains
Insulin effects on various tissues
1.Liver
Inhibits : glycogenolysis, Ketogenesis, gluconeogenesis
Stimulates: glycogen synthesis, triglyceride synthesis
2. Skeletal Muscle
Stimulates: glucose transport, amino acid transport
3. Adipose Tissue
Stimulates: triglyceride storage, glucose transports
Glucose disposal during fasting state
75% is non-insulin dependent: Liver GI, Brain
25% is insulin dependent in skeletal muscle
- glucagon is secreted to prevent hypoglycemia
Glucose Disposal during fed state
80-85% is insulin dependent in skeletal muscle
4-5% is insulin dependent in adipose tissue
Glucagon secretion is inhibited
Insulin inhibits release of fatty acids from adipose tissue
Glucose transporters
GLUT 1 (Km 1-2mM)
- constitutive and widely expressed throughout the tissue (also in Beta cells in the liver but small amount)
GLUT 2 (Km 15-20mM)
- constitutive and expressed in beta cells in the liver
GLUT 3 (Km <1mM)
- constitutive and expressed in neurons
GLUT 4 (Km 5mM)
- insulin- induced and found in the skeletal muscle adipocytes
Site of insulin production and secretion
Islets of Langerhans
Actions of pancreatic polypeptide hormones
- Glucagon
- this is secreted when blood glucose levels are low and it will stimulate glycogen breakdown to increase the blood glucose - Insulin
- which is released when glucose levels are hight and it stimulates the uptake and utilization of glucose - Amylin
- this is co secreted with insulin and it will slow gastric emptying, decrease food intake (make you feel full) and inhibit glucagon secretion - Somatostatin
- this is a general inhibitor of secretion
What are the 4 pancreatic polypeptide hormones
Glucagon, insulin, somatostatin, and amylin
Explain the process of producing insulin
Insulin is synthesized in the beta cells and is produced when proinsulin is cleaved (in 2 spots) by proconvertase which produces insulin and connecting peptide (c peptide) which get released in a 1:1 ratio
what are the two types of insulin sources
Recombinant human insulin
Human insulin cDNA in plasmid expressed in either E.coli or transformed yeast
- Advantages : it allows control of amino acid sequences and we are able to produce large batches and purify them
Why do we have so many different types of insulin
We want to mimic the natural secretion of insulin.
Natural insulin release it broken down into phase 1 and phase 2. By having different chemical properties of modified insulin we can use them in combination
Purpose
- provide convenience with dosing
- basal levels vs preprandial dose
Insulin treatments: Ultra rapid onset/ very short action
Lispro (Humalog)
Aspart (Novolog)
Glulisine (Apidra)
explain how Lente insulins worked
They would complex insulin and zinc together and the more complexed insulin was to zinc the more slowly the insulin would be absorbed
THESE ARE NO LONGER USED
Insulin Treatment: Rapid onset/ short action
Regular (R)
Insulin Treatment: Intermediate onset/ action
NPH (N)
Insulin Treatment: slow onset/ long action
Glargine (lantus)
Detemir (levemir)
Degludec (tresiba)
Lispro insulin (Humalog)
Ultra rapid onset/ very short action
Reversing portions of proline 28 (P28) and lysine 29 (K29) on insulin B chain which results in decreased self association (to be rapidly absorbed it must be in monomeric form)
- Place in therapy: Injected immediately before meals
NPH insulin
doesn’t have recombinant insulin
Its insulin bound to protamine which when injected the protamine is broken down by tissue proteases in the body and release insulin allowing for a slower absorption (1-1 1/2) and a long duration of action (24hrs)
Insulin Aspart (Novolog)
Human, except Proline 28 in B chain is switched to aspartate
Rapid onset: 5-15min, short duration
Injected immediately before meals
Insulin Glulisine (Apidra)
Human except Asn 3 and Lys 29 in B chain are switched to Lys and Glu
Rapid onset: 5-15 min, short duration
Injected immediately before meals
Insulin Glargine ( Lantus)
Changes:
Asn 21 of a- chain is changed to Gly
2 Arg residues added to the end of the B- chain (30&31)
- Basal Insulin
-Action: Glargine is slowly and steadily released from injection site over 24 hours - once daily injection
Insulin Detemir (Levemir)
Thr 30 of B chain is deleted and lys 29 is myristylated
Binds to serum albumin which provides a slow release and slow absorption
Insulin Degludec (Tresiba)
Thr 30 of B chain is replaced by gamma-Glu/C16 fatty acid
which binds to serum albumin allowing for slow release and absorption
Multi-dose insulin regimens
Fast onset, short acting taken before meals
Long, or intermediate acting taken at bedtime or at bet time and after breakfast
Mixing provides a transient preprandial bolus and a prolonged basal level in a single injection
Inhaled Insulin
Afrezza (Approved by FDA June 2014)
Regular Human insulin in dry powder form
Rapid onset, shorter duration of action than SC injection - used as pre-prandial insulin
CONTRAINDICATION - Patients with asthma and COPD, may reduce lung function
Routes of administration
Subcutaneous - all preparations
Insulin infusion pump - Buffer Regular, also rapid acting, (i.e. Lispro, Aspart, Glulisine)
IV- Regular (for severe hyperglycemia or ketoacidosis
Inhalation - Afrezza (not commonly used)
Types of patients using insulin
- Type 1 Diabetics
-Patients with ketosis and hyperosmolar coma - some type II diabetics
Mode of action of insulin in diabetic patients
Decrease liver glucose output
Increase fat storage
Increase glucose uptake
Adverse reactions to insulin
inside the body
Hypoglycemia - blood glucose <60 mg/dL
Signs and symptoms include:
weakness, sweating, hunger, tachycardia, increased irritability, tremor, blurred vision, seizures, coma, increased sympathetic output
TX
- treat with glucose or glucagon
Adverse reaction to insulin
skin
Lipodystrophy - changes in fat at over use of injection site
Lipoatrophy - Loss of fat in subcutaneous tissue
Lipohypertrophy - Accumulation of fat in subcutaneous tissue
Agents that increase blood glucose levels
Thyroid hormone, contraceptives, morphine, catecholamines, Calcitonin
Agents that decrease blood glucose
Ethanol, ACE inhibitors, Somatostatin, fluoxetine, anabolic steroids, beta adrenergic blockers
How does insulin secretion in type 2 diabetics differ from normal insulin release
In type two diabetics we do not see that peak of insulin that follows after a meal. We also refer to this peak as phase 1
Pathophysiology of type 2 diabetes
Insulin resistance and reduced insulin secretion
Pathophysiology of type 2 diabetes - Liver
After a meal usually in a normal patient you would see a peak in insulin secretion by the beta cells in the liver. In diabetes there is a blunting of this peak in response to a meal
Pathophysiology of type 2 diabetes - Skeletal muscles
Normal:
With an increase of plasma insulin levels you would see an increase in the utilization of glucose in the skeletal muscles
Type 2 diabetes:
The skeletal muscle is not taking up as much glucose like it usually would which also effects the excretion of glucose which has a huge effect on blood glucose levels
Pathophysiology of type 2 diabetes - Pancreatic islet
Normal
insulin normal inhibits glucagon secretion
Type 2 diabetics
glucagon secretion is not inhibited
Pathophysiology of type 2 diabetes - Adipose tissue (fat)
Normal
insulin will stimulate the storage of fat
Type 2 diabetics
Not stimulated
Agents that enhance insulin secretion
Sulfonylureas
and
Meglitinides
Sulfonylureas and Type 2 diabetes
Must have functioning beta cells
- These work to restore the first phase insulin release and increase beta cell sensitivity to glucose and increase glucose stimulated insulin release
Sulfonylureas MOA
These when taken will bind to the sulfonyurea receptors which closes the K+ channel. This closure will lead to decreased cell polarization of the membrane potential. This depolarization will lead to the opening of voltage sensitive Ca+ channels. With high levels of calcium now in the cell it will promote insulin release and increase the release of insulin.
First generation sulfonylureas
Tolbutamide (Orinase)
Duration - 6-12hrs
Tolazamide (Tolinase)
Duration - 12-14hrs
Chlorpropamide (Diabinese)
Duration - 24-72hrs
Second generation sulfonylureas
Glipizide (Glucotrol)
Duration - 12-24
Glyburide (Diabeta glynase)
Duration - 24
Glimepiride (amaryl)
24
Nateglinide (starlix)
Non sulfonylurea Katp channel blocker
- very specifi for Katp channels in pancrease vs CV tissue
Shorter t1/2 than prandin (less risk of hypoglycemia
