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USMLE STEP 1 > Diabetes and Obesity > Flashcards

Diabetes and Obesity Flashcards

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1
Q

Chemical characteristic stabilizing pro-insulin

A

Disulfide bonds

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2
Q

When is pro-insulin cleaved to insulin?

A

During exocytosis

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3
Q

Marker for insulin release

A

C peptide

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4
Q

What stops a large amount of insulin from reaching systemic circulation?

A

The pancreas drains into the portal system. There are many insulin receptors in the liver.

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5
Q

Describe the effect of glucose load on post-prandial glucose

A

No effect; post-prandial glucose is consistent despite different oral glucose loads. Insulin release is what changes.

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6
Q

Non-glycemic activators of insulin release

A

Incretins (GLP1, GIP), parasympathetic innervation (acetylcholine)

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7
Q

GLP1 full name and effects

A

Glucagon-like peptide 1; incretin (cAMP-dependent), decreases glucagon secretion, decreases appetite, and delays gastric emptying

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8
Q

GIP full name and effects

A

Glycagon-dependent insulinotropic polypeptide; incretin

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9
Q

How dos glucose enter the beta cells of the pancreas?

A

(Bidirectional) GLUT2

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10
Q

How does glucose trigger insulin release from beta cells?

A

The increased ATP/ADP ratio causes closing of ATP-sensitive K+ channels, causing depolarization. Calcium channels open and the influx causes insulin secretion.

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11
Q

How do catecholamines inhibit insulin release?

A

By blocking cAMP

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12
Q

What type of receptor is the insulin receptor?

A

Receptor tyrosine kinase

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13
Q

How does insulin reduce blood glucose?

A

1) Glucose uptake by insertion of GLUT4 in the membrane of muscle and adipose
2) Glucose usage by glycolysis
3) Glucose storage by glycogen synthesis (via protein kinase B activation of glycogen synthase kinase 3)
4) Promotes fatty acid synthesis

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14
Q

Non-glucose effects of insulin

A

1) Uptake of amino acids; activation of sodium potassium pump
2) Inhibition of triglyceride breakdown (glucose converted to glycerol backbone and joined with fatty acids from liver to synthesize more triglycerides)

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15
Q

Acanthosis nigricans etiology

A

Hyperinsulinemia in the context of insulin resistance stimulates the IGF-1 receptor in keratinocytes

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16
Q

Insulin resistance presentation

A

1) Abnormal glucose metabolism (most common)
2) Acanthosis nigricans
3) Hyperandrogenism (women only)
4) Abdominal obesity

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17
Q

GLP1 comes from the same gene as which protein?

A

Glucagon (different cleavage sites)

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18
Q

Which hormones inhibit glucagon release?

A

Insulin and somatostatin

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19
Q

Functions of glucagon

A

1) glycogenolysis in the liver

2) gluconeogenesis in the liver and kidney

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20
Q

Main source of glucose in post-absorptive state

A

Glycogenolysis in the liver (followed by gluconeogensis in the liver)

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21
Q

Hypoglycemia presentation

A

Blood glucose <60 mg/dL; adrenergic symptoms (tremor, palpitations, anxiety, sweating)

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22
Q

Neuroglycopenia presentation

A

Blood glucose <50 mg/dL; Cognitive impairment, behavioral changes, psychomotor abnormalities, seizure, coma

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23
Q

Type 2 DM diagnostic criteria

A

One of the following:
- fasting plasma glucose >126 mg/dL
- 2-hour after oral glucose tolerance test >200 mg/dL
HbA1C .6.5%

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24
Q

Glucose profile at A1C of 5%

A

below 100

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25
Glucose profile at A1C of 6%
120
26
Glucose profile at A1C of 7%
180
27
"Triumvirate" of type 1 DM
Beta cell dysfunction, increased hepatic production of glucose, and decreased glucose transport into muscle
28
How does type 2 dm cause atherosclerosis?
Adipocytes become resistant to the antilipolytic effect of insulin, so plasma free fatty acids increase. THese cause inflammatory and atherosclerotic cytokine production.
29
Treatment goals for type 2 DM
Reduce complications by lowering A1C to below 7%; manage cardiovascular risk factors
30
Major cause of death in type 2 DM
Cardiovascular (dyslipidemia)
31
Effect of intensive glucose control on vascular sequelae of type 2 DM
No effect on macrosvascular/CV mortality; lowers risk of microvascular complications
32
Autoantibodies in type 1 DM
Islet cell cytoplasm (ICA), islet antigen (IA), glutamic acid decarboxylase (GAD), zinc transporter 8 (ZnT8)
33
Cause of destruction in type 1 DM
T cell mediated destruction of beta cells; no evidence that autoantibodies are cytotoxic
34
HLA haplotypes observed in 90% of type 1 DM patients
DR3-DQ2 and DR4-DQ8
35
Autoimmune polyglandular syndrome type 1 (Whitaker)
Hypoparathyroidism, mucocutaneous candidiasis, adrenal insufficiency (need 2/3) and others
36
Autoimmune polyglandular syndrome type 2 (Schmidt)
adrenal insufficiency, type 1 DM, autoimmune thyroid disorder (need 2/3) and others
37
Perinatal factors implicated in type 1 DM
maternal age and birth order (higher risk in first born)
38
Type 1 DM presentation
Lack of insulin production, polyuria, polydipsia, weight loss, DKA, perineal candidiasis, cataracts
39
Mechanism of hyperglycemia in DKA
Insulin deficiency allows glucagon to stimulate glucagon production by the liver, unchecked. Severe hyperglycemia leads to osmotic diuresis and volume depletion.
40
Mechanism of ketoacidosis in DKA
Increased release of free fatty acids and their subsequent oxidation bu the liver generates ketone bodies. These cannot be cleared effectively by the kidney due to volume depletion
41
DKA signs/symptoms
Nausea/vomiting, hypothermia, tachycardia, Kussmaul breathing, ileus, acetone breath, AMS
42
DKA lab tests
Rothera's test (alkaline urine turns bright red when nitroprusside tablets are added); direct measurement of serum bea-hydroxybutarate; anion gap metabolic acidosis; hyperosmolality; elevated triglycerides
43
DKA treatment
Replace fluids, insulin for hyperglycemia, replace electrolytes
44
Hyperosmotic hyperglycemic nonketotic state
DKA-like but without ketoacidosis; risk of coma, AMS
45
Metformin class
Biguanides
46
Metformin- MOA
activates AMP kinase, leading to increased skeletal muscle glucose uptake and decreased hepatic gluconeogenesis by improving hepatic insulin sensitivity
47
Metformin- ADRs
diarrhea, nausea, abdominal pain, B12 deficiency, "risk of lactic acidosis" (from old biguanides). May cause weight loss.
48
Metformin- clearance
Renal
49
Metformin- contraindications
Renal dysfunction, liver dysfunction, acidosis
50
Thiazolidinediones- MOA
Decreases level of free fatty acids via PPARγ, reducing FFA mobilization. This indirectly causes increased uptake of glucose and improved hepatic insulin sensitivity
51
Thiazolidinediones- examples
Pioglitazone, rosiglitazone
52
Thiazolidinediones- ADRs
lower extremiety edema, CHF exacerbation, weight gain (FFAs), decreased bone density, myocardial infarction (rosiglitazone), bladder cancer (pioglitazone)
53
Secretagogues- MOA
Bind to sulfonylurea receptor 1 (SUR1), a subunit of the potassium channel on beta cells. This causes depolarization and increases insulin exocytosis.
54
Secretagogues- examples
Sulfonylureas: glipizide, glyburide, glimepiride (2nd generation drugs); Meglitinides: repaglinide, nateglinide, mitiglinide
55
Secretagogues- ADRs
Hypoglycemia, weight gain (sulfonylureas), CV disease (sulfonylyreas, via SUR2)
56
DPP4 inhibitors- MOA
Slow degradation of GIP and GLP1 by DPP4
57
DPP4 inhibitors- examples
Sitaglipin, linagliptin, alogliptin, saxagliptin
58
DPP4 inhibitors- ADRs
nausea, headache, possibly pancreatitis; | reduce dose in CKD
59
DPP4 inhibitors- metabolism
Renal clearance (except linagliptin which is cleared by the gut)
60
GLP1 agonists- MOA
GLP1 analog that is resistant to DPP4 degradation
61
GLP1 agonists- examples
Exenatide, liraglutide, dulaglutide, albiglutide
62
GLP1 agonists- ADRs
Nausea, diarrhea, constipation. May cause weight loss.
63
GLP1 agonists- contraindications
Thyroid C-cell hyperplasia, pancreatitis, personal/family history of medullary thryoid cancer. Reduce dose if CKD.
64
A-glucosidase inhibitors- MOA
Inhibits enzymatic breakdown of carbs intomonosaccaride units by pancreatic alpha-amylase and intestinal alpha-glucosidase hydrolase enzymes at the brush border. Sugars bypass small intestine and are delivered to the colon where absorption is slower.
65
A-glucosidase inhibitors- examples
Acarbose, miglitol
66
A-glucosidase inhibitors- metabolism
Acarbose is cleared by the gut and kidney. Miglitol is cleared by the kidney only.
67
A-glucosidase inhibitors- ADRs
Diarrhea, flatulence, bloating, abdominal pain
68
A-glucosidease inhibitors- contraindications
Liver disease, IBD, renal disease. Watch LFTs.
69
SGLT2 inhibitors- MOA
Stop glucose reabsorption by the kidney in the PCT
70
SGLT2 inhibitors- examples
Canaliflozin, dapagliflozin, empagliflozin
71
SGLT2 inhibitors- ADRs
polyuria, UTI, vulvovaginal candidiasis, dehydration, hypotension
72
SGLT2 inhibitors- metabolism
Cleared by gut and kidney
73
SGLT2 inhibitors- contraindications
CKD
74
Amylinomimetics- MOA
Amylin analog that binds to brain nuclei to increase satiety, decrease appetite, slow gastric emptying, and suppress glucagon
75
Amylinomimetics- examples
Pramlinitide
76
Amylinomimetics- ADRs
Nausea
77
Deposits found in pancreatic islet beta cells in patients with type 2 DM
Islet amyloid polypeptide (IAPP, or amylin)
78
Bile acid sequestrants- examples
Colesevalam
79
Bile acid sequestrants- ADRs
GI
80
D2R agonists- MOA (diabetes)
Given 2 hours after waking and may create a circadian peak in DA tone, which may result in increased insulin sensitivity
81
D2R agonists- examples
Bromocriptine
82
D2R agonists- ADRs
Nausea, headache
83
D2R agonists- contraindications
pregnant/nursing
84
Basal (long-acting) insulins
Glargine, detemir
85
Intermediate-acting insulin
Neural protamine Hagedorn (NPH; used as basal insulin)
86
Bolus (rapid-acting) insulins
Lispro, Aspart, Glulisine
87
Regular insulin (short-acting) use and dosing
Useful for grazing eating pattern or in patients with tube feeding/peritoneal dialysis. Dosed every 6-8 hours.
88
Type of basal insulin in combination insulin preparations
Neural protamine Hagedorn (NPH)
89
What might prolong the effects of insulin?
Kidney disease
90
Mechanisms for hyperglycemia-induced damage
1) overproduction of superoxide (ROS) by mitochondrial ETC 2) Intracellular production and accumulation of advanced glycosylated end products (AGEs), which diffuse out to modify extracellular molecules, bind the receptor for AGE (RAGE), and trigger inflammatory cytokines and growth factors 3) Activation of protein kinase C, leading to vascular damage 3) Acceleration of the aldose reductase (Polyol) pathway, which generates sorbitol and then fructose from glucose. This consumes NADPH and decreases glutathione, exacerbating ROS damage. 4) Increased hexosamine pathway activity, which generats UDP N-acetyl glucosamine. This is bad for vessels.
91
Mechanism of microvascular damage in diabetes
Hypercglycemia causes diffuse thickening of basement membranes, leading to distortion and eventual occlusion of capillaries.
92
Diabetic retinopathy- presentation
Intraretinal hemorrhages, cotton wool spots, hard exudates, microvascular abnormalities (microaneurysms, tortuous vessels, occluded vessels). New blood vessels if proliferative. Macular edema may occur in proliferative retinopathy.
93
Diabetic retinopathy- treatment
If macular edema is present, use VEGF imhibitors (bevacizumab, ranibizumab, aflibercept); panretinal photocoagularion in proliferative retinopathy
94
Diabetic nephropathy- presentation
Persistent albuminuria; mesangial expansion, glomerular BM thickening, podocyte injury, glomerular sclerosis (Kimmelstiel-Wilson lesion), decreased GFR
95
Diabetic neuropathy-presentation
Distal symmetric polyneuropathy (usually sensory), autonomic neuropathy, polyradiculopathies, mononeuropathies (CNIII, median nerve), acute painful neuropathies (treatment-induced)
96
Diabetic neuropathy- treatment
Antidepressants (duloxetine, amitriptyline), topical anasthetics (capsaicin, lidocaine), anticonvulsants (pregablin), footcare
97
Mechanism of marcrovascular complications in diabetes
Overproduction of VLDL in type 2 DM; slower clearance of TG-rich lipoproteins; enzymatic exchange of T from VLDL with cholesterol ester from LDL, leading to TG-rich LDL. TG-rich LDL is the preferred substrate for hepatic lipase, yielding small dense LDL. sdLDL are atherogenic.
98
Non-vascular diabetes complications
Diabetic cheiroarthropathy, Dupuytren's contracture, increased infection susceptibility, toenail onychomycosis, necrobiosis lipoidica, foot problems
99
What is adiponectin?
A protein hormone secreted by adipose cells. It is benficial and anti-inflammatory. Associated with weight loss.
100
From where is ghrelin secreted?
Fundus of the stomach
101
Ghrelin functions
Orexigenic; signals to hippocampal area, hedonic system, and homeostatic brain. Secreated at meal suppression.
102
Ghrelin dysfunction in obesity
Levels are low in the fasting state but are NOT suppressed after eating as they should be
103
How does GLP-1 promote satiety?
Inhibits orexigenic neuropeptide Y
104
"Hunger center" of the hypothalamus
Lateral hypothalamus
105
"Satiety center" of the hypothalamus
Ventromedial hypothalamus
106
How does leptin promote satiety?
Acts in the arcuate nucleus and stimulates POMC production. THis increases alpha-melanocyte stimulating hormone (aMSH), which acts on MC4-R and MC3-R, causing appetite suppression.
107
How does ghrelin promote hunger?
Ghrelin acts on arcute nucleus to increase release of agouti-related peptide, which inhibits MC4-R and stimulates the orexigenic pathway.
108
Serotonin (5HT2C) agonist anti-obesity medications
Lorcaserin, sibutramine, dexfenfluramine
109
Naltrexone- MOA
Acts on mu receptors
110
Liraglutide (and Rimonabont)- MOA
GLP-1 agonist
111
Topamax- MOA
Potentiates GABAergic neurons
112
Bupropion
Dopamine agonist
113
Phentermine- MOA
Inhibits sodium-dependent norepinephrine transportor, reducing NE uptake, as well as serotonin and DA uptake.
114
Phentermine- ADRs
Dry mouth, constipation, insomnia, palpitations, headache, irritability
115
Phentermine- contraindications
Active CV disease, HTN, cardiac arrhythmias, hyperthyroidism, glaucoma

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