Diabetes Hockerman Flashcards
1
Q
Three Ps of diabetes
A
Polydipsia, polyuria, polyphagia
2
Q
Mean age of T1DM diagnosis
A
12
3
Q
How is type 1 diabetes characterized
A
-Autoimmune response that specifically targets pancreatic cells
-Glucose intolerance
-No functioning insulin-secreting pancreatic beta cells
-Dependency on insulin and a tendency towards ketoacidosis
-Family history is often negative
4
Q
What percentage of beta cell mass must be lost in order for fasting blood glucose to increase from normal levels?
A
~70%
5
Q
Which autoantigen is present in 99% of type 1 diabetics?
A
islet antigen 2 (IA-2)
57% of non-diabetics who have this antigen will develop type 1 diabetes
6
Q
Consequences of lack of insulin
A
-Hyperglycemia - Decreased glucose uptake in cells where glucose uptake is insulin-dependent, decreased glycogen synthesis, increased conversion of amino acids to glucose
-Glucosuria - due to high blood glucose
-Hyperlipidemia - increased fatty acid mobilization from fat cells, increased fatty acid oxidation - ketoacidosis
-Uninhibited glucagon - increased glucagon levels in the presence of increased blood glucose levels
7
Q
Complications caused by diabetes
A
-Cardiovascular - micro and macro angiopathies
-Neuropathy - increased blood glucose levels lead to increased utilization of the polyol pathway (aldose reductase), water accumulation in neurons/reduced protection from oxidative damage
-Nephropathy - renal vascular changes and changes in the glomerular basement membrane
-Ocular - cataracts, retinal microaneurysms and hemorrhage
-Increased susceptibility to infections
8
Q
Current insulin therapy goals
A
-Keep average blood glucose levels below 150 mg/dL
-Prevent/delay onset of complications
-Increased risk of hypoglycemia
9
Q
How does hyperglycemia covalently modify proteins?
A
Oxidation products of glucose react irreversibly with proteins to form advanced glycation end-products (AGE)
10
Q
Complications caused by AGE
A
-Loss of normal protein function
-Acceleration of the aging process
-Theorized to account for many long-term complications of diabetes
11
Q
Percentage of type 2 diabetics that are obese
A
80%
12
Q
The typical age of onset for obese type 2 diabetics
A
Usually over 35
13
Q
The typical age of onset for non-obese type 2 diabetics
A
-Often under 25
-Maturity onset diabetes of the young (MODY)
14
Q
Cause of non-obese type 2 diabetes
A
Mutations in specific proteins
15
Q
Cause of obese type 2 diabetes
A
Insulin resistance/decreased BCM
16
Q
Mechanisms of cell damage initiated by hyperglycemia
A
-Polyol pathway
-Hexosamine pathway
-Protein kinase C pathway
-AGE pathway
17
Q
Role of alpha subunits
A
-The regulatory unit of the receptor represses the catalytic activity of the beta subunit
-Repression is relieved by insulin binding
18
Q
Role of beta subunits
A
-Contain the tyrosine kinase catalytic domains
-Autophosphorylation
19
Q
How does the insulin membrane receptor stimulate glycolysis, glucose uptake, and lipogenesis?
A
-The receptor phosphorylates PI3K which activates PKB causing induction of glycolysis
-PI3K also converts PIP2 to PIP3 which recruits PDK1 also resulting in glycolysis
20
Q
How does the insulin membrane receptor stimulate glucose uptake?
A
PI3K converts PIP2 to PIP3 which recruits PDK1 which is then able to activate aPKC which stimulates GLUT4 causing glucose uptake into skeletal muscles
21
Q
How does the insulin membrane receptor stimulate lipogenesis and cell growth/proliferation?
A
-Phosphorylation of PI3K induces lipogenesis
-The receptor also activates MAPK which leads to lipogenesis and cell growth/proliferation
22
Q
Effects of the insulin membrane receptor
A
-Increased glucose uptake
-Increased lipogenesis
-Increased glycolysis
-Increased glycogen synthesis
-Increased DNA + RNA synthesis (Cell growth/proliferation)
-Decreased gluconeogenesis
23
Q
Insulin effects on the liver
A
Inhibition of:
-Glycogenolysis
-Ketogenesis
-Gluconeogenesis
Stimulation of:
-Glycogen synthesis
-Triglyceride synthesis
24
Q
Insulin effect on skeletal muscle
A
Stimulation of:
-Glucose transport
-Amino acid transport
25
Insulin effect on adipose tissue
Stimulation of:
-Triglyceride storage
-Glucose transport
26
Characteristics of GLUT1
-Km 1-2
-Constitutive
-Widely expressed in beta cells
27
Characteristics of GLUT2
-Km 15-20
-Most predominant of the glucose transporters
-Constitutive
-Expressed in beta cells and liver
28
Characteristics of GLUT3
-Km <1
-Constitutive
-Expressed in neurons
29
Characteristics of GLUT4
-Km 5
-Insulin-induced
-Expressed in skeletal muscles and adipocytes
30
Actions of glucagon
-Stimulates glycogen breakdown
-Increases blood glucose
31
Actions of somatostatin
General inhibitor of secretion
32
Actions of insulin
Stimulates uptake and utilization of glucose
33
Actions of amylin
-Co-secreted with insulin
-Slows gastric emptying (slows absorption of glucose)
-Decreases food intake (makes you feel full)
-Inhibits glucagon secretion
34
How is insulin processed?
-Synthesized as a single peptide and deposited in secretory granules
-In secretory granules, is cleaved to A and B chains, and C (connecting) peptide by proconvertases
35
Lispro (Humalog) onset
0.25 hours
36
Lispro (Humalog) peak
0.5-1.5 hours
37
Lispro (Humalog) duration
6-8 hours
38
Aspart (Novolog) onset
0.25 hours
39
Aspart (Novolog) peak
1-3 hours
40
Aspart (Novolog) duration
3-5 hours
41
Glulisine (Apidra) onset
0.25 hours
42
Glulisine (Apidra) peak
0.5-1.5 hours
43
Glulisine (Apidra) duration
3-5 hours
44
Ultra rapid onset/very short action insulin
Lispro (Humalog), Aspart (Novolog), Glulisine (Apidra)
45
Rapid onset/short action insulin
Regular (R)
46
Regular insulin onset
0.5-1 hour
47
Regular insulin peak
2-4 hours
48
Regular insulin duration
8-12 hours
49
Intermediate onset/action insulin
NPH (N)
50
NPH onset
1-1.5 hours
51
NPH peak
4-12 hours (has very clear peak)
52
NPH duration
24 hours
53
Slow onset/long action insulin
Glargine (Lantus), Detemir (Levemir), Degludec (Tresiba)
54
Glargine (Lantus) onset
1-1.5 hours
55
Glargine (Lantus) peak
5 hours
56
Glargine (Lantus) duration
>24 hours
57
Detemir (Levemir) onset
1-2 hours
58
Detemir (Levemir) peak
4-9 hours
59
Detemir (Levemir) duration
>24 hours
60
Degludec (Tresiba) onset
1 hour
61
Degludec (Tresiba) peak
9 hours
62
Degludec (Tresiba) duration
>24 hours
63
Mechanism of action for NPH insulin
Insulins are bound to a protamine. Protamine is then dissolved by tissue proteases releasing free insulin. This results in a slow absorption and a long duration of action.
64
Characteristics of Lispro (Humalog)
-Reversing positions of P28 and K29 on insulin B chain results in decreased self-association (no hexamer formation)
-Place in insulin therapy - injected immediately before meals
65
Characteristics of Aspart (Novolog)
-Proline 28 in B chain is changed to Aspartate (disrupts dimerization)
-Injected immediately before meals
66
Characteristics of Glulisine (Apidra)
-Asn 3 and Lys 29 in B chain are switched to Lys and Glu
-Inject immediately before meals
67
Characteristics of Glargine (Lantus)
-Asn 21 of a-chain is changed to Gly
-2 Arg residues added to the end of the b-chain (30 and 31)
-Clear solution at pH of ~ 4.0: precipitates when neutralized
-Once daily injection
-No pronounced peak
68
Characteristics of Detemir (Levemir)
-Thr 30 of b-chain is deleted, and Lys 29 is myristylated (fatty acid attached)
-Binds serum albumin extensively (due to fatty acid)
-Injected once or twice daily
69
Characteristics of Degludec (Tresiba)
-Thr 30 of b-chain is replaced by gamma-Glu/C16 fatty acid
-Binds serum albumin extensively (due to fatty acid)
-Injected once daily
70
Common multi-dose insulin regimens
-Fast onset, short acting taken before meals
-Long, or intermediate taken at bedtime or at bed time and after breakfast
71
Common insulin mixture formulations
NPH + regular:
-Humulin 70/30
-Humulin 50/50
NPL (neutral protamine lispro) + Lispro
-Humalog 75/25
-Humalog 50/50
Ryzodeg (70% Degludec + 30% Aspart)
These give a transient preprandial bolus and a prolonged basal level in a single injection
72
Characteristics of Afrezza
-Regular Human Insulin in a dry powder inhalation
-Rapid onset, shorter duration of action the subq injection - used as pre-prandial insulin
73
What is Afrezza contraindicated in?
-Contraindicated in patients with asthma and COPD
-May reduce lung function (decreased FEV)
74
Routes of administration for insulin
-Subcutaneous - all preparations
-Insulin infusion pump - Buffered Regular also rapidly acting insulins
-IV - Regular (for severe hyperglycemia or ketoacidosis)
-Inhalation - Afrezza
75
Types of patients that use insulin
-Type 1 diabetics
-Patients with ketosis and hyperosmolar coma
-Some type 2 diabetics
76
What is the main adverse reactions to insulin?
-Hypoglycemia - blood glucose <60 mg/dL
-Lipodystrophy - lump of fat at over used injection site
-Lipohypertrophy - accumulation of fat in subcutaneous tissue
-Lipoatrophy - concavities in subcutaneous tissue
-Antibodies can be formed against insulin from insulin therapy
77
How to treat hypoglycemia?
Glucose or glucagon
78
What can cause hypoglycemia?
Too much insulin or not enough food
79
Agents that can increase blood glucose (especially in diabetics)
-Catecholamines
-Glucocorticoids
-Oral contraceptives
-Thyroid hormone
-Calcitonin
-Somatropin
-Isoniazid
-Phenothiazines
-Morphine
80
Agents that may increase the risk of insulin hypoglycemia
-Ethanol (#1 cause)
-ACE inhibitors
-Fluoxetine
-Somatostatin
-Anabolic steroids
-MAO inhibitors
-beta adrenergic blockers
-Vigorous, unaccustomed exercise
81
Treatment plan for T1DM
Insulin + diet + exercise
82
Treatment plan for T2DM
-Diet + exercise
-Diet + exercise + antidiabetic drugs
-Diet + exercise + insulin
83
Agents that enhance insulin secretion
Sulfonylureas and meglitinides
84
Examples of meglitinides
-Nateglinide
-Repaglinide
85
Why do sulfonylureas only work in T2DM?
Must have functioning beta cells
86
Function of sulfonylureas
-Restore first phase insulin release
-Increase beta cell sensitivity to glucose and increase glucose stimulated insulin release
87
Effects of sulfonylureas on beta cell insulin release
-Binds to sulfonylurea receptors
-Inactivates K+ channel
-Decreased cell polarization
-Activates voltage sensitive Ca+ channels
-Increase Cai++ and activity of microfilaments
-Increased exocytosis of insulin containing granules
88
Pharmacophore of sulfonylureas
Sulfonylurea group (im not paying for premium look it up for image)
89
Tolbutamide (Orinase) potency
1
90
Tolbutamide (Orinase) Duration
6-12 hours
91
Tolazamide (Tolinase) potency
5
92
Tolazamide (Tolinase) duration
12-14 hours
93
Chlorpropamide (Diabinese) potency
6
94
Chlorpropamide (Diabinese) duration
14-72 hours
95
Glipizide (Glucotrol) potency
100
96
Glipizide (Glucotrol) duration
12-24 hours
97
Glyburide or Glibenclamide (DiaBeta, Glynase) potency
150
98
Glyburide or Glibenclamide (DiaBeta, Glynase) duration
24 hours
99
Glimepiride (Amaryl) potency
~150
100
Glimepiride (Amaryl) duration
24
101
First generation sulfonylureas
Tolbutamide, Tolazamide, Chlorpropamide
102
Second generation sulfonylureas
Glipizide, Glyburide/Glibenclamide, Glimepiride
103
Pharmacophore of meglitinides
Phenylalanine group (im not paying for premium look it up for image)
104
What is Repaglinide (Prandin)?
A non-sulfonylurea hypoglycemic agent (Glinide)
105
Repaglinide (Prandin) mechanism of action
Like sulfonylureas
106
Repaglinide (Prandin) onset
-Quick onset with short duration of action (t1/2 - 1 hour)
-Take tablet before meal
107
Characteristics of Nateglinide (Starlix)
-Non-sulfonylurea KATP channel blocker (Glinide)
-Very specific for KATP channels in pancreas vs CV tissue
-Shorter half-life than Prandin so less risk of hypoglycemia
-Synergistic with metformin
108
Possible adverse events from sulfonylureas
-Lasting and prolonged hypoglycemia (due to long half life) (this has been misdiagnosed as stroke)
-Risk of cardiovascular events/mortality?
-GI problems
-Weight gain and increased numbers of secondary failures (can see a decreased ability to make insulin because of the stress on beta cells)
109
Drug interactions with sulfonylureas
-Salicylates
-Phenylbutazone
-Sulfonamides
-Clofibrate
-Oral contraceptives
-Corticosteroids
-Epinephrine
-Thiazide diuretics
-Corticosteroids
-Thyroid
110
Agents that enhance the incretin effect
-GLP-1R agonists
-GLP-1 and GIP dual agonist
-DPP-IV inhibitors
-Amylin analogs
111
What is the incretin effect?
Oral glucose stimulates a larger insulin response than IV glucose in humans because of receptors in the intestines that bind to glucose and result in insulin secretion
112
Benefits of GLP-1 agonists
-Reduce hyperglycemia with low risk of hypoglycemia
-Weight loss
-Increase beta cell mass
113
Example of GLP-1 agonists
Exenatide (Exendin 4; Byetta), Liraglutide (Victoza), Dulaglutide (Trulicity), Lixisenatide (Adlyxin), Semaglutide (Ozempic), Semaglutide oral (Rybelsus)
114
Warnings for all GLP-1 analogs
-Nausea and vomiting
-Pancreatitis
-Risk of thyroid C-cell tumors
-Contraindicated in patients with a family history of medullary thyroid cancer
115
Characteristics of Exenatide (Exendin 4; Byetta)
-Activates GLP-1 receptor
-Enhances first phase secretion
-Longer half-life than GLP-1
-Twice daily injections or once per week injections (Bydureon)
-Can be co-administered with metformin, TzDs, or sulfonylureas
116
Characteristics of Liraglutide (Victoza)
-GLP-1analog
-Half-life of 13 hours
-Subq daily
-Can be co-administered with metformin, TzDs, and sulfonylureas
-Monitor calcitonin levels
117
Characteristics of Dulaglutide (Trulicity)
-GLP-1 agonist
-Injected subq once a week
-GLP-1 agonist peptides are slowly released from IgG Fc domain by reduction of disulfide bonds in linker region
118
Characteristics of Lixisenatide (Adlyxin)
-GLP-1 receptor agonist
-Injected subq daily before breakfast
119
Characteristics of Semaglutide (Ozempic)
-GLP-1 receptor agonist
-Injected subq once per week
-Extensively bound to serum albumin - t1/2 ~ 1 week
120
Characteristics of Semaglutide oral (Rybelsus)
-Orally available GLP-1 receptor agonist
-Oral bioavailabilty - o.4-1.0%
-Absorbed from stomach
-Dosed once daily
121
Characteristics of Mounjaro (Tirzepatide)
-Full GIP receptor agonist
-Biased GLP-1 receptor agonist preferential coupling to cAMP over beta-arrestin
-Reduces internalization (desensitization) of GLP-1 receptor to maintain GLP-1 effect
-Weekly subq injection
-Purported to reduce A1c and body weight more effectively than GLP-1 receptor agonists
122
What is Dipeptidyl Peptidase 4 (DPP-4)
The enzyme that degrades GLP-1
123
Examples of DPP-4 inhibitors
Sitagliptin (Januvia), Saxagliptin (Onglyza), Linagliptin (Tradjenta), Alogliptin (Nesina)
124
Characteristics of DPP-4 inhibitors
-Administered orally - once daily
-Reduce hyperglycemia and HgbA1c
-Low risk of hypoglycemia
-Considered weight neutral
-May be co-administered with metformin, TzDs (all are available in combination with metformin)
125
Metabolism and excretion of Januvia and Nesina
Not extensively metabolized, excreted in urine (kidney)
126
Metabolism and excretion of Tradjenta
Not extensively metabolized, excreted in feces (liver)
127
Metabolism and excretion of Onglyza
CYP3A4/5 substrate, major metabolite active, excreted in urine (kidney)
128
Side effects of DPP-4
-Nausea
-Vomiting
-Constipation
-Headache
-Severe skin reactions
-Pancreatitis
-Joint pain
-Heart failure
-Reduced white blood cell counts - infections
-Potential increased risk of cancers
129
Characteristics of Pramlintide (Symlin)
-Amylin analog
-Normally co-secreted with insulin
-Slows gastric emptying, decreases fluid intake, inhibits glucagon secretion
-Blunts post-meal rise in blood glucose
-Used in conjunction with insulin - increased subq
-Useful in both type 1 and type 2 diabetes
130
Examples of alpha-glucosidase inhibitors
Acarbose, Miglitol
131
Examples of SGLT2 inhibitors
Canagliflozin, Empagliflozin, Dapagliflozin, Ertugliflozin
132
Mechanism of action of alpha-glucosidase inhibitors
Decrease the absorption of carbohydrate from the intestine via inhibition of gut alpha glucosidases
133
Adverse effects of alpha glucosidase inhibitors
Both: GI -- diarrhea, nausea, flatulence
Acarbose: risk of liver damage at doses > 100mg tid
134
Strategy for SGLT2 inhibition
Blocks SGLT2 transporter in the kidney that prevents reuptake of glucose to the blood
135
Pharmacophore of SGLT2 inhibitors
Glucose attached
136
Characteristics of SGLT2 inhibitors
-Orally active
-Indicated for Type 2 diabetes as an adjunct to diet and exercise
-Decreases A1c as monotherapy with metformin, sulfonylureas
-Significant weight loss observed with monotherapy
137
Warning for SGLT2 inhibitors
-Increased risk of genital/UT infections
-Increased urine flow/volume depletion/hypotension
-Increased rusk of diabetic ketoacidosis (DKA)
-Contraindicated in patients with renal impairment
-Increased risk of lower limb amputation
138
Example of biguanide
Metformin
139
Examples of thiazoladinediones
Pioglitazone, Rosiglitzone
140
Causes of insulin resistance
-Polymorphism in insulin signaling pathway proteins (rare)
-Obesity - especially accumulation of fat in the abdominal cavity
-Inactivity
141
Effect of insulin resistance on certain tissue types
-Skeletal muscle - impaired glucose uptake
-Adipose tissue - impaired glucose uptake, impaired inhibition of lipolysis, mobilization of FAs to other tissues
-Liver - impaired inhibition of glucose output (via gluconeogenesis or glycogenolysis)
142
Role of fatty acids in obesity-induced insulin resistance
-Free fatty acid (FFA) levels are increased in obese
-Acutely raising FFA levels causes insulin resistance (IR)
-Acute lowering of plasma FFA levels reduces chronic IR
The predominant effect is on insulin-stimulated glucose transport
143
What does metformin do?
-Classified as an antihyperglycemic agent
-Decreases blood glucose concentrations in T2DM without the concentration falling below normal
-Increases the efficiency or sensitivity to insulin in liver, fat, and muscle cells
144
Advantages of biguanides over sulfonylurea
-Rarely causes hypoglycemia
-Rarely causes weight gain
145
Mechanism of action of metformin
Activator of AMP-activated kinase (AMPK)
146
What does metformin do in the liver
Blocks FBPase which prevents the conversion of fructose-1,6-bisphosphate to fructose-6-phosphate
147
What does metformin do in the liver
Promotes GTPase activity of Rab causing it to dissociate from GLUT4 allowing it to stay on the cell surface to transport glucose back into the cell
148
What is metformin contraindicated in?
Disorders that increase the tendency toward lactic acidosis
149
Adverse effects of metformin
-Decreased vitamin B-12 absorption
-GI discomfort
150
Effects of metformin on blood lipid profile
-Decreased serum triglycerides
-Decreased serum LDL
-Reduces risk of adverse cardiovascular
151
Thiazolidinediones mechanism of action
-Deccrease insulin resistance or improve target cell response to insulin
-Activators of peroxisome proliferator-activated receptor gamma (PPARgamma), a transcription factor
152
Targets of thiazolidinediones
Adipocytes:
-Enhances adipocyte differentiation
-Enhances FFA uptake into subq fat
-reduces serum FFA
-Shifts lipids into fat cells from non-fat cells
Liver:
-Enhances glucose uptake
-Reduces hepatic glucose production
Skeletal muscle:
-Enhances glucose uptake
153
Warnings for thiazolidinediones
-Restricted prescribing due to cardiovascular toxicities
-Actos is associated with an increased risk of bladder cancer
-Some hepatotoxicity -- check liver function
-Do not cause hypoglycemia
-FDA warning - both are contraindicated in class II or IV heart failure
154
Factors regulated by the activation of PPARgamma
-Resistin - Elevated in type 2 diabetes
-Adiponectin - Decreased in type 2 diabetes
-TNFalpha - Increased in type 2 diabetes
155
What is resistin?
Stimulates glucose export by liver and insulin resistance
156
What is adiponectin?
Reduces blood glucose and insulin resistance
157
What is TNFalpha?
Stimulates lipolysis in WAT and insulin resistance
158
What happens to insulin response in early pregnancy
Increased insulin response e.g. hypoglycemia in T1D
159
What happens to insulin response in late pregnancy
Reduced insulin sensitivity because of growth of fetus
160
What is gestational diabetes
-Defined as hyperglycemia during pregnancy during pregnancy in otherwise non-diabetic women
-Diagnosed with 24-28 week OGTT
-Affects 2-10% of pregnancies
161
When does gestational diabetes usually appear?
Usually appears around week 24 of gestation - in the rapid growth stage of gestation, after fetus has formed - not associated with defects in fetal development
162
Complications that occur from gestational diabetes
-Damage to baby during birth (particularly shoulders)
-Neonatal hypoglycemia
-Breathing problems - high glucose or high insulin levels can delay maturation of lungs
-Increased risk of developing type 2 diabetes
163
Maternal insulin resistance in gestational diabetes mellitus
-Inability of target tissue to respond to insulin
-Insulin doesn't cross the placenta, but glucose!
-Factors secreted by the placenta into the maternal circulation
164
What are the placental hormones suspected in gestational insulin resistance
CRH-cortisol:
-Both increase as pregnancy progresses
-Glucocorticoids oppose insulin action
Progesterone:
-Increases as pregnancy progresses
Placental GH (GH-V):
-Released during half of gestation
-May contribute to insulin resistance
Placental lactogens:
-Increases as pregnancy progresses
-85% identical to GH-contributes to insulin resistance
165
GDM is predictive of T2D later in life. Why?
Exposes the body's inability to react to insulin resistance
166
Hormones that increase beta cell mass during pregnancy
Prolactin:
-Increases as pregnancy progresses
-Stimulates beta cell proliferation
Placental lactogen:
-Activates PRL (high aff) and GH receptors (low aff)
167
Treatment of gestational diabetes
-Diet: small meals, complex carbs, avoid sugary foods
-Insulin : gold standard - doesn't cross placenta
-Glyburide: works- but may harm fetus
-Metformin: works- crosses placenta but does not harm fetus
-Thiazolidinediones- NOT USED
