MLS Exam #1 (M)

What two hormones are stored in the posterior pituitary (remember, these do not have a true axis)?

ADH; oxytocin

Where is ADH produced & what are some of its effects?

Hypothalamus (but stored in posterior pituitary); vasoconstriction, stimulate free H2O retention in kidney (aka concentrate urine), stimulate ACTH release

What are the 2 forms of diabetes insipidus (DI)? What is each form characterized by?

1) Central (Neurogenic) DI: actual decrease in ADH production/release, often due to trauma of some kind

2) Nephrogenic DI: normal ADH production, but resistance to its effects at the kidney (aka ADH resistance)

What is a medication that can very commonly cause nephrogenic DI?

Lithium

What is the general pathophysiology of DI?

Decreased ADH production (central DI) or ADH resistance (nephrogenic DI) leads to decreased renal reabsorption of free H2O, ultimately causing patient to produce large volumes of very dilute urine

What are some classic s/sxs of DI?

Polydipsia, polyuria (very very dilute), +/- hypernatremia (high blood osmolality)

When taking a fasting ADH level, what results suggest central vs. nephrogenic DI?

Central: ADH will be low

Nephrogenic: ADH will be high

When performing a vasopressin challenge test, what results suggest central vs. nephrogenic DI?

Central: sxs likely improve w/ administration of DDAVP

Nephrogenic: sxs will not improve

Remember: vasopressin (DDVAP) is another name for ADH

When is a brain MRI indicated to assess DI?

For suspected central cases (body unable to produce (hypothalamus) or release (pituitary) ADH for some reason)

What are our first-line treatments for central & nephrogenic DI, respectively? What is another med we may add to refractory cases?

Central: synthetic DDVAP (desmopressin)

Nephrogenic: hydrochlorothiazide (HCTZ) diuretic

Refractory: indomethacin (an NSAID)

What is a med specifically indicated to treat lithium-induced DI?

Amiloride

If we are giving a patient IV fluid replacement for their DI, what is important to keep in mind?

We need to use hypotonic solutions, otherwise we may make cause/exacerbate hypernatremia

Although there are many many causes of syndrome of inappropriate ADH (SIADH), what are 2 common ones?

Various meds such as MDMA (ecstasy); small cell lung cancer (ectopic ADH)

What is the general pathophysiology of SIADH? What does it result in (specifically)?

An abnormal increase in ADH production leads to increased renal reabsorption of free H2O, ultimately resulting in euvolemic hypotonic hyponatremia

Again, what is the most common clinical presentation of SIADH?

Hyponatremia (nausea, malaise, lethargy, HA, disorientation, seizure, coma, respiratory arrest)

Is it usually necessary to draw a patient's ADH level if we suspect SIADH?

No, not usually

What are some general lab findings we expect to see with SIADH (Na+ levels, serum osmolality, urinary output, urine specific gravity)?

Sodium: decreased

Serum osmolality: decreased

Urine output: very low

Urine SG: increased

What is our treatment goal in SIADH?

Treat underlying cause & return Na+ to 125-130 mEq/L (normal level)

In general, what is panhypopituitarism?

Deficiency of ALL hormones secreted by the anterior pituitary; tends to happen in a very predictable pattern (GH --> FSH/LH --> TSH --> ACTH); it is also possible for the posterior pituitary to be affected

How would we go about working up a patient with suspected panhypopituitarism?

We would want to check both pituitary & end-organ hormone levels for all hormones, plus perform the appropriate stimulation tests to confirm

What is the treatment for panhypopituitarism?

Treat underlying cause + HRT (especially cortisol - hydrocortisone!!)

In general, what is empty sella syndrome (ESS)? Do patients always have sxs?

Enlargement of sella turcica + filling w/ CSF; can compress pituitary, but often patients are asymptomatic

What is a classic MRI sign of ESS?

"Infundibulum sign" (pituitary stalk is present, it's just compressed)

How would we go about working up a patient with suspected ESS?

We would want to check both pituitary & end-organ hormone levels for all hormones, plus perform the appropriate stimulation tests to confirm

What is insulin released by, and what triggers its release?

β-cells in the Islets of Langerhan found in the pancreas in response to elevated blood glucose levels

What is the effect of insulin on adipose tissue?

Enhances glucose uptake by adipocytes via lipogenesis (glucose -> glycerol -> TGs) & inhibits lipolysis

Why is it significant that insulin inhibits lipolysis in adipocytes?

It is the most sensitive pathway of insulin action (1st thing to be affected if insulin levels change)

What is the effect of insulin on skeletal muscle?

Enhances glucose uptake by myocytes via glycogenesis (glucose -> glycogen) as well as increasing protein synthesis & preventing protein catabolism

Why is the liver unique in terms of glucose uptake?

It is NOT insulin-mediated as in adipocytes and myocytes

What is the effect of insulin on the liver?

Glycogenesis (glucose -> glycogen) UP TO A POINT (it is saturable); after this point excess glucose is turned into glycerol which combines w/ FFAs to form TGs (lipogenesis - just like adipocyte pathway)

Insulin also inhibits gluconeogenesis & ketogenesis in the liver

How does down-regulation of insulin receptors perpetuate IR?

As insulin levels increase/remain high, the body says "woah I don't need all these insulin receptors" and down-regulates them, perpetuating resistance

How does IR perpetuate itself in terms of adipose tissues/adipocytes, and what does this lead to?

Adipocytes are unable to uptake glucose due to the IR, so they increase lipolysis in an attempt to provide alternative (non-glucose) sources of fuel (i.e. FFAs) creating a downward spiral of lipotoxicity

High FFA levels worsen IR through a variety of ways such as gluconeogenesis, ketogenesis, etc.

How does IR perpetuate itself in terms of skeletal muscle/myocytes, and what does this lead to?

Just like with adipose tissue, myocytes are unable to uptake glucose due to the IR, so they increase glycogenolysis & protein catabolism in an attempt to provide alternative (non-glucose) sources of fuel (i.e. FFAs, AAs)

These FFAs & AAs are subsequently used in processes like gluconeogenesis & ketogenesis, worsening the IR

Although glucose uptake is NOT insulin-mediated in the liver, how does IR still perpetuate itself here?

Hyperinsulinemia (due to IR) causes glycogenesis to occur and rapidly saturate the liver. Following this, the liver will convert all of the remaining excess glucose into TGs via lipogenesis (glucose -> glycerol -> TG) which are carried to adipose tissue via VLDLs and stored there (this is all normal liver response to insulin, it's just happening quickly here because there's high insulin)

Once in the adipose tissue, however, all these extra TGs are now susceptible to the disordered effects of IR on adipocytes: lipolysis -> lipotoxicity -> increased gluconeogenesis & ketogenesis, etc.

By definition, what is gluconeogenesis?

Generation of glucose molecules from non-CHO sources (pyruvate, lactate, AAs, glycerol, FFAs, etc.)

By definition, what is ketogenesis?

Oxidation of FFAs or AAs to produce ketone bodies

In general, what is obesity?

Adipocyte hyperplasia (increase in number) and hypertrophy (increase in lipid deposition within them)

Which type of adipose tissue (visceral or subcutaneous) has more adverse metabolic effects and is considered to be more harmful?

Visceral

What BMI values are considered to be normal, overweight, and obese, respectively?

Normal: 18.5-24.9 kg/m²

Overweight: 25-29.9 kg/m²

Obese: ≥ 30 kg/m² (class III morbid obesity = ≥ 40)

How does obesity contribute/perpetuate IR in terms of adipose tissue?

By definition, obesity is hyperplasia & hypertrophy of adipose tissue. In IR, adipocytes activate lipolysis in an attempt to create alternative (non-glucose) sources of fuel. FFAs, a product of lipolysis, perpetuate IR in several ways

Why is visceral adipose tissue considered to be more metabolically active & thus more harmful?

It is (1) less sensitive to insulin & thus cannot prevent lipolysis as effectively and (2) is more sensitive to hormones like glucagon, which increases BG

What is the relationship between how obesity & adipokine dysregulation perpetuates IR?

Obesity causes the release of several pro-inflammatory adipokines, stimulate production of CRP & fibrinogen (clotting), & decreases other adipokines such as leptin leading to hunger & overfeeding

Many of these pro-inflammatory adipokines directly perpetuate IR via their MOAs but it's beyond our scope

What is the first step/sign we will see in the disease progression of insulin resistance & T2DM?

Postprandial hyperinsulinemia

What is the best dyslipidemia-related marker that we have of IR?

Hypertriglyceridemia (high TGs)

JUST KNOW: increased sdLDLs, HTN, hyperuricemia, inflammation, & hypercoagulability are all side effects of IR/hyperinsulinemia. There are several complex physiologic reasons this happens

What 2 diseases does metabolic syndrome put patients at greatly increased risk of?

1) T2DM

2) CVD

What is the main pathophysiologic driving force behind the development of metabolic syndrome? What is the greatest risk factor?

Insulin resistance; obesity

What is the diagnostic criteria for metabolic syndrome as defined by NCEP ATP III?

Three or more of the following:

1) Central obesity (WC > 40 in for males, > 35 in for females)

2) Hypertriglyceridemia (≥ 150 mg/dL)

3) Low HDL (< 40 for males, < 50 for females)

4) High BP (≥ 130 systolic or ≥ 85 diastolic)

5) Fasting hyperglycemia (≥ 100 mg/dL)

If any of these values are normal but the patient is being currently treated for the condition, they still fulfill the criteria

JUST KNOW: nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), PCOS, and obstructive sleep apnea (OSA) are all highly associated with IR

What is acanthosis nigricans?

Darkened patches of velvet-like skin that is a classic PE finding of IR

What is the most important lifestyle change a patient can make to lose weight? What about maintain weight loss?

Lose weight: diet (caloric reduction)

Maintain weight loss: increase physical activity

What class of medication is very effective for weight loss in patients with metabolic syndrome?

GLP-1 receptor agonists

What class of medication is very effective for dyslipidemia therapy in patients w/ metabolic syndrome?

Statins

What class(es) of medication(s) is/are very effective for hypertension management in patients w/ metabolic syndrome?

ACEi/ARBs

What class(es) of medication(s) is/are very effective for hyperglycemia management in patients w/ metabolic syndrome?

Biguanides (metformin); thiazolidinediones (TZDs)

Actually more important than the GLP agonists for managing IR because they address the underlying cause - they increase insulin sensitivity

What is the general pathophysiology of Type 1 DM?

Autoimmune destruction of β-cells leads to an inability to produce sufficient insulin

What is the difference between Type 1A and Type 1B DM?

Type 1A: >95% of cases, autoantibodies identified

Type 1B: <5% of cases, idiopathic

What is the general pathophysiology of Type 2 DM?

Gradual progression of insulin resistance leads to a vicious cycle of worsening loss of blood glucose control

In terms of speed of onset, how do T1DM and T2DM differ?

Type 1 generally occurs very rapidly from insult->disease while Type 2 generally progresses slowly over many years

What is latent autoimmune diabetes of adulthood (LADA)?

Atypical, milder form of Type 1 DM that develops in adulthood; patient will gradually lose β-cell function over time and will eventually require insulin

What is gestational diabetes mellitus (GDM)?

Form of diabetes that develops in pregnant women

What is maturity-onset diabetes of the young (MODY)?

Autosomal dominant trait that leads to impaired insulin secretion; primarily affects non-obese patients <25 y/o (no clinical evidence of IR)

JUST KNOW: there are various genetic mutations & secondary causes such as endocrine disorders/tumors, pancreatic disorders, & medications that can also produce DM, but these are not nearly as common

What are some common s/sxs of DM (all types)?

Polyuria, polydipsia, polyphagia w/ weight loss (T1), weakness/fatigue, blurred vision, vulvovaginitis/balanitis, peripheral neuropathy, nocturnal enuresis (T1), or completely asymptomatic (T2)

What fasting plasma glucose (FPG) levels signify normal, impaired glucose tolerance (IGT), & DM, respectively?

Normal: < 100 mg/dL

IGT: 100-125 mg/dL

DM: ≥ 126 mg/dL

What 2-hr postprandial glucose levels signify normal, IGT, & DM, respectively?

Normal: < 140 mg/dL

IGT: 140-199 mg/dL

DM: ≥ 200 mg/dL

What HbA1c levels signify normal, IGT, & DM, respectively?

Normal: < 5.7%

IGT: 5.7-6.4%

DM: ≥ 6.5%

Why is coronary disease (CAD, MI) relevant to DM?

It is the leading cause of death in Type 2 patients

JUST KNOW: although coronary disease may be the leading cause of death in Type 2 diabetic patients, cerebrovascular disease and peripheral vascular disease - including gangrene - are also VERYY common in these patients and must be considered on examination - these patients are many times at risk of developing these conditions

At what BP threshold do we decide to treat patients for HTN? What is our preferred class of meds for this, and what is our BP goal for them?

≥ 130/80; ACEi or ARBs; goal = < 130/80

What is our preferred class of meds to treat dyslipidemia in diabetic patients?

Statins

What are 2 classes of meds that have CV benefit for Type 2 diabetic patients?

SGLT2 inhibitors; GLP-1 receptor agonists

How is diabetic nephropathy relevant to DM? How do we screen diabetic patients for it?

It is the 2nd leading cause of CKD (HTN is first); annual UACR

What is finerenone?

Agent similar to aldosterone (but is non-steroidal) that is indicated very specifically for T2DM patients w/ CKD + albuminuria on maximally-tolerated ACEi/ARB

How is peripheral neuropathy relevant to DM? How do we screen for it?

It is the most common complication of DM; annual diabetic foot exam + monofilament

How does peripheral neuropathy usually present?

In a "stocking-glove" pattern, sensory loss usually occurs first followed by motor changes (like decreased reflexes)

What is Charcot foot arthropathy?

Deformity of the foot secondary to the motor changes of diabetic neuropathy that leaves the patient susceptible to callus & ulcer formation

What are the only 2 FDA-approved drugs available for diabetic neuropathy?

Pregabalin (an anti-epileptic) and duloxetine (an SNRI)

What are 4 possible complications of central (autonomic) neuropathy in diabetic patients?

Orthostasis; gastroparesis; erectile dysfunction; neurogenic bladder

What are some eye pathologies that can develop secondary to DM? How do we screen for these?

Diabetic cataracts; glaucoma; diabetic retinopathy (proliferative vs. non-proliferative); annual ophthalmologist visits

What is disseminated granuloma annulare?

Ring/arc-shaped lesions that are raised & sharply-defined; may develop secondary to DM; easily mistaken for tinea

What is diabetic dermopathy?

Light brown scaly patches that do not hurt, open up, or itch (d/dx from venous stasis); may develop secondary to DM

What is necrobiosis lipoidica diabeticorum (NLD)?

Appears similar to diabetic dermopathy but is fewer, larger, deeper, & may be itchy, painful, or open up; may develop secondary to DM

What is bullosis diabeticorum?

Diabetic blisters that may develop secondary to DM

What is digital sclerosis?

Development of thick, waxy skin that can lead to joint stiffness; may develop secondary to DM

What are some MSK pathologies that can develop secondary to DM?

Hyperuricemia/gout; osteoporosis; inflammation or glycosylation of collagen & synovium (tightens up tissues); Charcot's deformity; digital sclerosis

According to the most recent guidelines, at what age do we begin screening asymptomatic adults for T2DM? If results are normal, how often do we repeat testing?

Beginning at age 35; every 3 years

What are 4 groups of people who warrant T2DM screening at any age?

1) Overweight/obese patients w/ ≥ 1 additional risk factor(s)

2) Patients w/ HIV

3) Patients on high-risk meds

4) Patients w/ a hx of pancreatitis

If a patient has a hx of GDM, how often/how long do they require T2DM screening for?

Every 1-3 years for life

As a Clinical Science refresher, what are our options to screen for T2DM?

HbA1c, FGP, 2-hr PP OGTT are all appropriate

What group of children warrant screening for T2DM? When do we begin this, and how often is it done?

Overweight/obese w/ ≥ 1 additional risk factor; begin after age 10 onset of puberty; every 3 years

Although it's not very common, what are 2 situations that may warrant a patient to be screened for T1DM?

1) Positive fhx of T1DM in a first-degree relative

2) Hx/fhx of autoimmunity

What is the most important obligation of the clinician who provides initial care to the diabetic patient?

EDUCATION of the patient and the family

In terms of medication, what are the mainstays of therapy for Type 1 and Type 2 DM, respectively?

Type 1: insulin

Type 2: metformin (caution w/ renal dysfunction)

Although HbA1c goals must be individualized to the patient, what are our general targets for most non-pregnant patients according to the ADA and AACE, respectively?

ADA: < 7%

AACE: < 6.5%

What are our general FBG & 1-2-hr postprandial glucose targets for most patients, respectively?

FBG: 80-130 mg/dL

1-hr: < 180 mg/dL

2-hr: < 150 mg/dL

What is the most common treatment complication in diabetic patients? How is it treated?

Hypoglycemia (particularly if they're on insulin therapy); PO CHO ingestion if able, parenteral glucagon if emergency

What are some s/sxs of hypoglycemia?

Jitteriness/shaking (1st to appear), tachycardia, palpitations, sweating, nausea, irritability, confusion, HA/fatigue, seizure, LOC/coma

What common anti-HTN med can contribute to "hypoglycemic unawareness?"

β-blockers

What is the Somogyi effect?

Patient experiences hypoglycemia overnight due to heightened insulin level (counter-regulatory hormones respond by raising BG); presents as persistent/recurring hyperglycemia in morning despite therapy