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USMLE STEP 1 > Diabetes and Obesity > Flashcards

Diabetes and Obesity Flashcards

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USMLE® Step 1 flashcards
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
Q

Glucose profile at A1C of 6%

A

120

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26
Q

Glucose profile at A1C of 7%

A

180

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27
Q

“Triumvirate” of type 1 DM

A

Beta cell dysfunction, increased hepatic production of glucose, and decreased glucose transport into muscle

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28
Q

How does type 2 dm cause atherosclerosis?

A

Adipocytes become resistant to the antilipolytic effect of insulin, so plasma free fatty acids increase. THese cause inflammatory and atherosclerotic cytokine production.

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29
Q

Treatment goals for type 2 DM

A

Reduce complications by lowering A1C to below 7%; manage cardiovascular risk factors

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30
Q

Major cause of death in type 2 DM

A

Cardiovascular (dyslipidemia)

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31
Q

Effect of intensive glucose control on vascular sequelae of type 2 DM

A

No effect on macrosvascular/CV mortality; lowers risk of microvascular complications

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32
Q

Autoantibodies in type 1 DM

A

Islet cell cytoplasm (ICA), islet antigen (IA), glutamic acid decarboxylase (GAD), zinc transporter 8 (ZnT8)

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33
Q

Cause of destruction in type 1 DM

A

T cell mediated destruction of beta cells; no evidence that autoantibodies are cytotoxic

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34
Q

HLA haplotypes observed in 90% of type 1 DM patients

A

DR3-DQ2 and DR4-DQ8

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35
Q

Autoimmune polyglandular syndrome type 1 (Whitaker)

A

Hypoparathyroidism, mucocutaneous candidiasis, adrenal insufficiency (need 2/3) and others

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36
Q

Autoimmune polyglandular syndrome type 2 (Schmidt)

A

adrenal insufficiency, type 1 DM, autoimmune thyroid disorder (need 2/3) and others

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37
Q

Perinatal factors implicated in type 1 DM

A

maternal age and birth order (higher risk in first born)

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38
Q

Type 1 DM presentation

A

Lack of insulin production, polyuria, polydipsia, weight loss, DKA, perineal candidiasis, cataracts

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39
Q

Mechanism of hyperglycemia in DKA

A

Insulin deficiency allows glucagon to stimulate glucagon production by the liver, unchecked. Severe hyperglycemia leads to osmotic diuresis and volume depletion.

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40
Q

Mechanism of ketoacidosis in DKA

A

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

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41
Q

DKA signs/symptoms

A

Nausea/vomiting, hypothermia, tachycardia, Kussmaul breathing, ileus, acetone breath, AMS

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42
Q

DKA lab tests

A

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

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43
Q

DKA treatment

A

Replace fluids, insulin for hyperglycemia, replace electrolytes

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44
Q

Hyperosmotic hyperglycemic nonketotic state

A

DKA-like but without ketoacidosis; risk of coma, AMS

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45
Q

Metformin class

A

Biguanides

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46
Q

Metformin- MOA

A

activates AMP kinase, leading to increased skeletal muscle glucose uptake and decreased hepatic gluconeogenesis by improving hepatic insulin sensitivity

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47
Q

Metformin- ADRs

A

diarrhea, nausea, abdominal pain, B12 deficiency, “risk of lactic acidosis” (from old biguanides). May cause weight loss.

48
Q

Metformin- clearance

A

Renal

49
Q

Metformin- contraindications

A

Renal dysfunction, liver dysfunction, acidosis

50
Q

Thiazolidinediones- MOA

A

Decreases level of free fatty acids via PPARγ, reducing FFA mobilization. This indirectly causes increased uptake of glucose and improved hepatic insulin sensitivity

51
Q

Thiazolidinediones- examples

A

Pioglitazone, rosiglitazone

52
Q

Thiazolidinediones- ADRs

A

lower extremiety edema, CHF exacerbation, weight gain (FFAs), decreased bone density, myocardial infarction (rosiglitazone), bladder cancer (pioglitazone)

53
Q

Secretagogues- MOA

A

Bind to sulfonylurea receptor 1 (SUR1), a subunit of the potassium channel on beta cells. This causes depolarization and increases insulin exocytosis.

54
Q

Secretagogues- examples

A

Sulfonylureas: glipizide, glyburide, glimepiride (2nd generation drugs);
Meglitinides: repaglinide, nateglinide, mitiglinide

55
Q

Secretagogues- ADRs

A

Hypoglycemia, weight gain (sulfonylureas), CV disease (sulfonylyreas, via SUR2)

56
Q

DPP4 inhibitors- MOA

A

Slow degradation of GIP and GLP1 by DPP4

57
Q

DPP4 inhibitors- examples

A

Sitaglipin, linagliptin, alogliptin, saxagliptin

58
Q

DPP4 inhibitors- ADRs

A

nausea, headache, possibly pancreatitis;

reduce dose in CKD

59
Q

DPP4 inhibitors- metabolism

A

Renal clearance (except linagliptin which is cleared by the gut)

60
Q

GLP1 agonists- MOA

A

GLP1 analog that is resistant to DPP4 degradation

61
Q

GLP1 agonists- examples

A

Exenatide, liraglutide, dulaglutide, albiglutide

62
Q

GLP1 agonists- ADRs

A

Nausea, diarrhea, constipation. May cause weight loss.

63
Q

GLP1 agonists- contraindications

A

Thyroid C-cell hyperplasia, pancreatitis, personal/family history of medullary thryoid cancer. Reduce dose if CKD.

64
Q

A-glucosidase inhibitors- MOA

A

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
Q

A-glucosidase inhibitors- examples

A

Acarbose, miglitol

66
Q

A-glucosidase inhibitors- metabolism

A

Acarbose is cleared by the gut and kidney. Miglitol is cleared by the kidney only.

67
Q

A-glucosidase inhibitors- ADRs

A

Diarrhea, flatulence, bloating, abdominal pain

68
Q

A-glucosidease inhibitors- contraindications

A

Liver disease, IBD, renal disease. Watch LFTs.

69
Q

SGLT2 inhibitors- MOA

A

Stop glucose reabsorption by the kidney in the PCT

70
Q

SGLT2 inhibitors- examples

A

Canaliflozin, dapagliflozin, empagliflozin

71
Q

SGLT2 inhibitors- ADRs

A

polyuria, UTI, vulvovaginal candidiasis, dehydration, hypotension

72
Q

SGLT2 inhibitors- metabolism

A

Cleared by gut and kidney

73
Q

SGLT2 inhibitors- contraindications

A

CKD

74
Q

Amylinomimetics- MOA

A

Amylin analog that binds to brain nuclei to increase satiety, decrease appetite, slow gastric emptying, and suppress glucagon

75
Q

Amylinomimetics- examples

A

Pramlinitide

76
Q

Amylinomimetics- ADRs

A

Nausea

77
Q

Deposits found in pancreatic islet beta cells in patients with type 2 DM

A

Islet amyloid polypeptide (IAPP, or amylin)

78
Q

Bile acid sequestrants- examples

A

Colesevalam

79
Q

Bile acid sequestrants- ADRs

A

GI

80
Q

D2R agonists- MOA (diabetes)

A

Given 2 hours after waking and may create a circadian peak in DA tone, which may result in increased insulin sensitivity

81
Q

D2R agonists- examples

A

Bromocriptine

82
Q

D2R agonists- ADRs

A

Nausea, headache

83
Q

D2R agonists- contraindications

A

pregnant/nursing

84
Q

Basal (long-acting) insulins

A

Glargine, detemir

85
Q

Intermediate-acting insulin

A

Neural protamine Hagedorn (NPH; used as basal insulin)

86
Q

Bolus (rapid-acting) insulins

A

Lispro, Aspart, Glulisine

87
Q

Regular insulin (short-acting) use and dosing

A

Useful for grazing eating pattern or in patients with tube feeding/peritoneal dialysis. Dosed every 6-8 hours.

88
Q

Type of basal insulin in combination insulin preparations

A

Neural protamine Hagedorn (NPH)

89
Q

What might prolong the effects of insulin?

A

Kidney disease

90
Q

Mechanisms for hyperglycemia-induced damage

A

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
Q

Mechanism of microvascular damage in diabetes

A

Hypercglycemia causes diffuse thickening of basement membranes, leading to distortion and eventual occlusion of capillaries.

92
Q

Diabetic retinopathy- presentation

A

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
Q

Diabetic retinopathy- treatment

A

If macular edema is present, use VEGF imhibitors (bevacizumab, ranibizumab, aflibercept); panretinal photocoagularion in proliferative retinopathy

94
Q

Diabetic nephropathy- presentation

A

Persistent albuminuria; mesangial expansion, glomerular BM thickening, podocyte injury, glomerular sclerosis (Kimmelstiel-Wilson lesion), decreased GFR

95
Q

Diabetic neuropathy-presentation

A

Distal symmetric polyneuropathy (usually sensory), autonomic neuropathy, polyradiculopathies, mononeuropathies (CNIII, median nerve), acute painful neuropathies (treatment-induced)

96
Q

Diabetic neuropathy- treatment

A

Antidepressants (duloxetine, amitriptyline), topical anasthetics (capsaicin, lidocaine), anticonvulsants (pregablin), footcare

97
Q

Mechanism of marcrovascular complications in diabetes

A

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
Q

Non-vascular diabetes complications

A

Diabetic cheiroarthropathy, Dupuytren’s contracture, increased infection susceptibility, toenail onychomycosis, necrobiosis lipoidica, foot problems

99
Q

What is adiponectin?

A

A protein hormone secreted by adipose cells. It is benficial and anti-inflammatory. Associated with weight loss.

100
Q

From where is ghrelin secreted?

A

Fundus of the stomach

101
Q

Ghrelin functions

A

Orexigenic; signals to hippocampal area, hedonic system, and homeostatic brain. Secreated at meal suppression.

102
Q

Ghrelin dysfunction in obesity

A

Levels are low in the fasting state but are NOT suppressed after eating as they should be

103
Q

How does GLP-1 promote satiety?

A

Inhibits orexigenic neuropeptide Y

104
Q

“Hunger center” of the hypothalamus

A

Lateral hypothalamus

105
Q

“Satiety center” of the hypothalamus

A

Ventromedial hypothalamus

106
Q

How does leptin promote satiety?

A

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
Q

How does ghrelin promote hunger?

A

Ghrelin acts on arcute nucleus to increase release of agouti-related peptide, which inhibits MC4-R and stimulates the orexigenic pathway.

108
Q

Serotonin (5HT2C) agonist anti-obesity medications

A

Lorcaserin, sibutramine, dexfenfluramine

109
Q

Naltrexone- MOA

A

Acts on mu receptors

110
Q

Liraglutide (and Rimonabont)- MOA

A

GLP-1 agonist

111
Q

Topamax- MOA

A

Potentiates GABAergic neurons

112
Q

Bupropion

A

Dopamine agonist

113
Q

Phentermine- MOA

A

Inhibits sodium-dependent norepinephrine transportor, reducing NE uptake, as well as serotonin and DA uptake.

114
Q

Phentermine- ADRs

A

Dry mouth, constipation, insomnia, palpitations, headache, irritability

115
Q

Phentermine- contraindications

A

Active CV disease, HTN, cardiac arrhythmias, hyperthyroidism, glaucoma

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