PHR 938 - Block 2 kaitlyn

prediabetes

higher than normal blood sugars, but not high enough to diagnose with diabetes

- high prevalence, most unaware that they have it

- very high risk for developing diabetes and cardiovascular disease

do you always progress to diabetes if you have prediabetes?

not always

- 25% progress to diabetes

- 50% remain in abnormal glycemic state

- 25% revert to normal glycemic state

- people with both impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) are at double the risk of developing diabetes

prediabetes lifestyle modifications

- aim for 5-7% reduction in weight to reduce risk

- nutrition therapy

- physical activity

- smoking cessation

- psychosocial care

- sleep health

- diabetes self-management education and support (DSMES)

prediabetes medications

there is no FDA approved agent with a specific indication for T2DM prevention

options (off-label):

- metformin, a-glucosidase inhibitors, GLP-1 agonists, TZDs, insulin, valsartan, testosterone

- weight loss medications (orlistat, phentermine, GLP-1 RAs)

is metformin effective in prediabetes?

not as effective (1/2) as lifestyle modifications

- it is more effective in younger pts, obese pts, higher FPG, higher A1C, and people with previous gestational diabetes

National Diabetes Prevention Program

- year long dietary and lifestyle program focused on long-term results

- certified centers around the country

- professional and social support

- cost varies by center. insurance often will cover the program

criteria:

18+, overweight, not diagnosed with T1/T2, and not currently pregnant AND meet 1 of these:

- diagnosed with prediabetes

- previous gestational diabetes

- high risk on prediabetes test

general nutrition guidelines

- emphasize fruits, vegetables, whole grains, lean protein, low-fat or non-fat dairy

- limit saturated fat, trans fatty acids, cholesterol, sodium, and added sugars

- achieve a balance of carbs throughout the day

- consume concentrated sweets in moderation

- include proteins and fats as well as carbs at meals and snacks

physical activity requirements

children:

- 60+ min/day of moderate-vigorous intensity aerobic activity

- vigorous muscle-strengthening and bone-strengthening activities 3 days/week

most adults with T1 and T2 diabetes:

- 150 of moderate-vigorous intensity aerobic activity

immunization recommendations

- pneumococcal

> PCV20: get once

- hep B series (under 60 or at risk)

- Tdap

- zoster

- HPV (<26 or 27-45 if risk factors)

- COVID-19

- flu (annual)

foot care

- comprehensive foot exam annually to check for ulcers/ loss of sensation

- if previous foot issues: foot exam at EVERY visit

- examine: skin, deformities, neuro assessment, vascular assessment

glycemic goals in the hospital

140-180

when to initiate insulin in the hospital

when pt has persistent hyperglycemic (2+ readings) of 180+ mg/dL

- stricter goals if they can be achieved without hypoglycemia

who has higher glucose goals in the hospital?

- terminally ill

- pts with severe comborbidities

- inpatient care where frequent BG monitoring/ close nursing supervision isn't possible

factors to account for when dosing insulin in the hospital

- type of diet ordered (PO, NPO, TPN, tube feed)

- medications causing hyperglycemia

- weight-based dosing

- home glycemic regimens

- degree of stress response

- kidney function

how is BG monitored in the hospital?

- PO pts: BG check before each meal and at bedtime

- NPO pts: BG check every 6 hours

- pts on IV insulin: BG check every 30 mins - 2 hours

insulin dosing: non-critically ill pts

- if on insulin at home: use TDD upon admission -> use 70-80% of TDD while hospitalized

- if not on insulin at home: dose by body weight

> 0.4 units/kg (normal weight)

- use SQ rapid or short acting AFTER meals

> or give every 6 hours if no meals are given

rapid insulin

Lispro (Humalog)

Aspart (Novolog)

Glulisine (Apidra)

normal insulin (regular)

Humulin R

Novolin R

basal insulin

Glargine (Lantus, Toujeo, Basaglar, Semglee)

how to split basal and rapid units? (PO pts)

basal dose = 50% of TDD

rapid dose = 50% of TDD

+ rapid-acting correction insulin

how to split basal and regular units? (tube/ TPN pts)

basal dose = 30% of TDD

regular insulin bolus = 70% of TDD - give every 6 hours

+ regular insulin correction

how to split basal and rapid units? (NPO pts)

basal dose = 50% of TDD

HOLD bolus until nutrition is established

+ regular insulin correction

insulin dosing: critically ill pts

- continuous IV insulin

- initiate when glucose is 180+ mg/dL

- maintain 140-180 mg/dL

how to transition from IV to SQ insulin

- administer 70-80% of IV TDD

- divide basal and bolus doses 50/50

- give a dose of SQ basal insulin 2 hours before d/c IV insulin

endocrine system

glands that control many of the body's activities by producing hormones

- affects metabolism, growth, water/electrolyte balance, reproduction, and behavior

3 components of the endocrine system

1. glands - ductless

- not anatomically connected to the target site

2. hormones - several classes with differing characteristics

3. target organs - contain hormone specific receptors

- hormone-receptor complex initiates steps that produce biological effects

hormone

chemical messengers, mostly those manufactured by the endocrine glands, that are produced in one tissue and affect another

3 classes of hormones

1. steroid

2. tyrosine derivatives

3. peptides and proteins

- glycoproteins

5 ways hormones get to their site of action

1. endocrine:

released by gland -> circulation -> target organ

(insulin, thyroid)

2. neuroendocrine:

secreted by neuron -> circulation -> target organ

(growth hormone, ADH, oxytocin)

3. paracrine:

secreted by cells -> extracellular fluid -> affects nearby cells of a different type

(FSH, GnRH)

4. autocrine:

secreted by cells -> extracellular fluid -> affects function of same type of cell

(prostaglandins, IL-1)

5. intracrine:

produced by and acts within a single cell

pulsatile release of hormones

some hormones (esp hypothalamic → pituitary) are secreted in bursts (pulses) rather than constant levels

- prevents desensitization/down-regulation of receptors.

-ex: GnRH must be pulsatile to stimulate LH/FSH release

- allows body to fine-tune physiologic responses (growth, reproduction, stress).

3 ways hormone secretion is controlled

1. negative feedback

- biological response suppresses hormone secretion

2. positive feedback

- needed to gather momentum for a specific outcome

(childbirth, ovulation)

3. circadian rhythms

- diurnal (daily, sleep/wake) or infradian (longer, menstrual cycle)

negative feedback system

hypothalamus produces releasing factors that stimulate the pituitary gland

↓

trophic hormones produced that stimulate target organs

↓

hormone production provides negative feedback to hypothalamus

↓

pituitary decreases releasing factor and trophic hormone production

- ↓ hormone levels = negative feedback is released and releasing factor production increases again

3 types of endocrine disorders

1. hormone deficiency

- too little

- due to: destruction of target organ cells, autoimmune response, genetic factors, lack of precursors/ enzymes

- ex: type 1 diabetes = no insulin production

2. hormone excess

- too much

- due to: tumors that overproduce, receptor overstimulation, or antibodies that trigger receptor action

- ex: hyperinsulinemia

3. hormone resistance

- doesn't work

- due to: desensitization of target cells, receptor fails to signal machinery

- ex: type 2 diabetes

how are hormone receptors regulated?

up-regulation: greater production of receptors or associated proteins

- the target cell is MORE responsive to the hormone

down-regulation: inactivation, destruction, decreased production of receptors or associated proteins

- target cell is LESS responsive to the hormone

these work in tandem to maintain steady levels

steroid

hormone class

- derived from: cholesterol

- synthesized in: adrenal cortex, gonads, placenta

- stored: not stored

- released: upon synthesis by diffusion out of the cell

- solubility: lipid soluble, bound to binding proteins in plasma (not free)

- t1/2: 20 min-24 hrs (binding proteins extend)

- receptor: intracellular (cytosolic or nuclear)

> crosses plasma membrane

- ex: reproductive hormones, cortisol, vit D

intracellular receptors

receptors located inside the cell rather than on its cell membrane

proteins/ peptides

hormone class

- synthesized: as inactive pre-prohormones

> cleaved to prohormones before storage (active)

- stored: in secretory granules in cytoplasms

- released: into interstitial fluid or circulation

- solubility: water soluble, no binding proteins

- t1/2: 4 min-2 hrs

- receptor: membrane bound GCPR

> does not cross plasma membrane

- ex: insulin, glucagom, GLP-1, growth hormones

glycoproteins

hormone class (subunit of proteins)

- contain 2 subunits: a common a subunit and a distinct B subunit

- ex: TSH, LH, FSH, hCG

- 200+ amino acids

- glycosylation -> alpha carbohydrate side chain added

G-protein coupled receptors (GPCR)

a cell-surface transmembrane receptor that works with the help of a G protein

- contain 7 transmembrane spanning segments

- the N terminus faces the extracellular space and contains the ligand-binding domain

- the C terminus is on the cytosolic side and is associated with 2nd messenger generating G-proteins

- 2nd messenger systems mediate a series of steps leading to the final hormonal action

- effects can be inhibitory or stimulatory

Gs, Gi, and Gq 2nd messenger system

Gs: α-subunit activated adenylate cyclase -> increases cAMP production

Gi: α-subunit inhibits adenylate cyclase -> decreases cAMP production

Gq: α-subunit activates PLCβ -> increased IP3 -> increases cytoplasmic Ca

Gi/Gs pathway

adenyl cyclase (AC) stimulation

↓

formation of cAMP

↓

activates protein kinase A (PKA)

↓

phosphorylates proteins that mediate hormonal activity

Gq pathway

phospholipase C (PLC) activation

↓

phospholipids split into diacylglycerol (DAG) and inositol triphosphate (IP3)

↓

activation of protein kinase C (PKC)

↓

alters activity of enzymes that mediate hormonal activity

GPCR internalization/ desensitization

internalization: receptor pulled into cell → recycled or degraded

desensitization: receptor less responsive → GRK phosphorylates → arrestin blocks signaling

prevents receptor overstimulation

biased agonism

ligand preferentially activates one signaling pathway over another (e.g., G protein vs. arrestin).

- can fine-tune drug effects → more therapeutic, fewer side effects.

enzyme-linked hormone receptors

some receptors have intrinsic enzyme activity and don't need 2nd messengers to work

- enzymatic activity may come directly from the receptor interaction (on cytosolic side) OR from an enzyme closely associated with the receptor

-ex: leptin receptor, insulin receptor

tyrosine derivatives: catecholamines

hormone class

- synthesized: from tyrosine (amino acid) in the adrenal medulla

- stored: in secretory granules

- solubility: water soluble, ~50% circulate free, ~50% loosely conjugated (albumin)

- t1/2: 1-3 mins

- receptor: GPCR

- ex: dopamine, norepinephrine, epinephrine

tyrosine derivatives: thyroid hormones

hormone class

- synthesized: from tyrosine (amino acid) in the thyroid gland

- stored: in thyroid gland (bound to thyroglobulin)

- released: by diffusion in response to thyroid-stimulating hormone (TSH)

- solubility: bound to thyroxine

- t1/2: T3=2.5 days T4=6-7 days

- receptor: intracellular (cytosolic or nuclear)

3 classes of hormones review

steroids:

- no storage

- diffuses across cell membrane

- enter interstitial fluid -> blood stream

- 90% bound to albumin/ binding globulins in plasma

peptides:

- generally stored as prohormones

- secretory vesicles fuse w cell membrane -> contents extruded into interstitial fluid or blood stream by exocytosis

catecholamines:

- stored in secretory granules

- rapid burst in response to stimuli

- soluble in plasma -> rapidly metabolized

hormone binding review

- affects blood levels

- bound hormone = inactive and protected from degradation (serves as hormone reservoir)

- depends on amount of binding protein available

- can also be taken up into tissues or bound to receptors

clearance review

hormones are cleared by:

- metabolic destruction by enzymes in blood/ tissues

- binding within tissues

- excretion by liver into bile

- excretion by the kidneys into urine

half-lives:

- steroids - hours

- catecholamines - seconds

- peptides - minutes

(steroids > thyroid hormones > peptides > catecholamines)

endocrine hypothalamus

- functions as a command center integrating information from the body and its environment

- most daily functions are influenced by hypothalamic signals + responses in the pituitary

- regulation is dynamic and adapts to changes

hypothalamus signals

signals to the pituitary to secrete hormones

- if the hormone ends in -rh, it comes from the hypothalamus (TRH, Gnrh, gh-rh)

pituitary structure

anterior and posterior lobe

- sit below the hypothalamus

- 2 hormones (oxytocin and vasopressin) are produced in the hypothalamus and stored in the posterior pituitary

- 6 hormones are secreted by the anterior pituitary

releasing hormones (RH)

- synthesized via Parvicellular neurons and travel via a portal system to the anterior pituitary -> stimulate production of pituitary trophic hormones

- posterior pituitary hormones are produced by magnocellular neurons in the hypothalamus -> travel to the posterior pituitary to be stored in nerve terminal vesicles

the pituitary gland has a portal vascular system similar to...

the liver

pulsatile vs circadian secretion

pulsatile: intermittent bursts over short periods of time

- ex: LH release from anterior pituitary

circadian: follows a 24 hour cycle

- ex: cortisol peaks in the morning and decreases through the day

hypothalamic releasing stimulatory hormones

1. thyroid-releasing hormone (TRH)

- peptide of 3 AA

- stimulates secretion of TSH

2. gonadotropin-releasing hormone (GnRH)

- single chain of 10 AA

- stimulates secretion of FSH and LH

3. corticotropin-releasing hormone (CRH)

- single chain of 41 AA

- stimulates secretion of ACTH

4. growth hormone-releasing hormone (growth hormone RH)

- single chain of 44 AA

- stimulates secretion of growth hormone

hypothalamic releasing inhibitory hormones

1. growth hormone inhibitory hormone (somatostatin)

- single chain of 14 AA

- inhibits secretion of growth hormone

2. prolactin-inhibiting hormone (PIH)

- dopamine

- inhibits secretion of prolactin

posterior pituitary hormones

1. vasopressin (antidiuretic hormone, ADH)

- formed in supraoptic nucleus of hypothalamus

- controls blood pressure, rate of water excretion

- stimulated by: low BP, salty/low water, RAS activation

2. oxytocin

- formed in paraventricular nucleus of hypothalamus

- positive feedback effect during child labor, milk expression

- have similar structures

diabetes insipidus

deficiency of vasopressin (antidiuretic hormone, ADH)

- may be neurogenic or nephrogenic

- treatment: desmopressin (synthetic ADH)

growth hormone

AKA somatotropin

hormone secreted by anterior pituitary gland that stimulates growth

- a protein composed of 191 AAs

- similar structure to prolactin

- t1/2: 20 minutes

growth hormone regulation

the hypothalamus produces:

growth hormone-releasing hormone (GH-RH)

and

growth hormone inhibitory hormone (somatostatin)

- acts directly on body tissues (liver, adipose, bone, muscle)

somatotropin vs somatostatin

somatotropin: growth hormone (GH)

- a protein hormone produced by the anterior pituitary gland

somatostatin: growth hormone-releasing inhibiting factor (GH-RF)

- a peptide hormone produced by the hypothalamus

effects of growth hormone

direct effects on: adipose, liver, skeletal, bone

- bone elongation promoted at epiphyseal plates

indirect effects via IGF-1: ↑ glucose uptake, ↑ AA synthesis, ↑ protein synthesis

life-time pattern of growth hormones

greatest at puberty

declines in advanced age

3 disorders of growth hormone (GH) release

1. gigantism - excess GH before puberty

- primarily due to anterior pituitary tumor

2. dwarfism - GH deficiency before puberty

- panhypopituitarism - decrease secretion of ALL pituitary hormones

3. acromegaly - excess GH after puberty

- bones thicken, soft tissues grow

obesity

having an excess amount of body fat

- due to: appetite dysregulation, abnormal energy balance, endocrine dysfunction

- associated symptoms: joint pain, altered metabolism, sleep apnea

- leads to: T2DM, CV, cancer, osteoporosis, PCOS, infertility, NAFLD/MAFLD, dyslipidemia

how to calculate BMI

weight (kg) / height (m^2)

lb → kg = lb/2.2

ft → in

in → cm = in x 2.54

cm → m = cm/100

m^2

BMI classification of obesity

underweight <18.5

normal 18.5 - 25

pre-obesity 25- 30

obesity ≥30

- obesity class I 30 - 35

- obesity class II 35 - 40

- obesity class III ≥40

what BMI classifies someone as obese?

≥30

edmonton obesity staging system (EOSS)

classes obesity based in morbidity and functional limitations

- stage 0-4 with 4 being end stage for medical, mental, and functional complications

- used to predict risks and benefits for obesity management

why do some people gain weight easily and others don't?

- genetics

- behavioral factors

- hormonal factors

- sleep patterns

- eating habits

highest prevalence of adult obesity in what population?

non-hispanic black

is obesity a chronic disease?

yes, and requires long-term management + ongoing care and support

hormone appetite signaling

orexigenic (increases appetite)

- ghrelin

anorexigenic (decreases appetite)

- CCK

- GLP-1

- GIP

- amylin/ insulin/ glucagon

- PP

- leptin

- adiponectin

3 types of eating

1. homeostatic: eating for hunger

- GLP-1, GIP, amylin, PYY ↑ satiety; ghrelin ↑ appetite

2. hedonic: eating for pleasure

- cannbinoid, opioid, and dopamine receptors involved

3. executive function: deciding to eat

- higher order brain regions override homeostatic drive

- thoughts ⇌ behavior ⇌ feelings

hunger and satiation signals in the brain

1. circumventricular organs

- a "window" in the brain with no BBB = can sense nutrients and hormones in circulation

↓

2. ventricle

- circulating CSF contains metabolic signals

↓

3. nucleus tractus solitarius

- vagus afferent nerve terminates and sends meal information straight from the gut

+

4. arcuate nucleus

- drug target neuron populations:

> POMC/CART - satiation

> NPY/AgRP - hunger

hypothalamic appetite signaling

arcuate nucleus (ARC): key appetite regulation center

NPY/AgRP neurons: ↑ appetite (orexigenic) → inhibit satiety pathway (POMC/CART).

POMC/CART neurons: ↓ appetite (anorexigenic) → activate MC4R in PVN to suppress feeding.

- balance between these pathways regulates food intake.

dorsal vagal complex (hindbrain) appetite signaling

- composed of NTS, area postrema, dorsal motor nucleus of vagus

- integrates gut-brain signals (CCK, GLP-1, vagal input)

- communicates with hypothalamus (ARC, PVN)

- helps regulate meal size & satiety

NTS neuronal populations appetite regulation

- central GLP-1 neurons: Inhibit food intake, signal satiety

- catecholaminergic (NE) neurons: Relay visceral sensory input, influence feeding

- other peptides: CCK, POMC, etc. contribute to satiety signal

t- he NTS integrates these → sends info to hypothalamus & dorsal vagal complex

obesity associated perturbations in gut-brain axis

brain:

- blunted neuronal activation

- inflammation, gliosis, and altered neuropeptide expression

- reduces sensing of vagal signals

gut:

- altered gut hormone release

- intestinal hyperpermeability

- microbial dysbiosis

- a resistance to satiation hormones, nutrients, and vagal afferent input in obesity → cannot sense body's nutrient needs

set point

the point at which an individual's "weight thermostat" is supposedly set

- when the body falls below this weight, an increase in hunger and a lowered metabolic rate may act to restore the lost weight

- takes months-years to challenge this

resting metabolic rate (RMR)

how much energy you burn at rest

- will decrease with weight loss as compensation to remain at set point weight

brain signals in a calorie deficit

- strong drive to increase hunger and reduce energy expenditure to restore weight

- brain sends signals that promote hunger

↑ NPY/AgRP (orexigenic, hunger-promoting)

↓ POMC/CART (anorexigenic, satiety)

obesity alters neuro-molecular mechanisms that regulate reward

- in obesity, feelings of reward for pleasurable stimuli are decreased

- upon dietary change/ weight loss, feelings of reward for palatable food are increased, making it harder to resist

__% increase in mortality is associated with every _ BMI point increase above 25

30%

5

fatty liver

metabolic-dysfunction associated liver disease (MASLD)

- strong correlation with metabolic health and obesity

the __ and __ are primary central energy regulating sites that integrate information about blood (hormones, nutrients) and neuronal input (gut vagal afferents)

hypothalamus (POMC/CART)

hindbrain (where vagal afferent nerve terminates, area postrema)

risks for metabolic dysfunction (insulin resistance, dyslipidemia) go up with waist size that is greater than __ cm for women or __ cm for men

women - 88 cm

men - 102 cm

treatment guidelines for obesity

picture

at what BMI is someone a candidate for pharm therapy?

≥30

or ≥27 with comorbidities

behavioral interventions for obesity

the foundation to obesity treatment

- improved food choices

- increased physical activity

- patient-led health tracking

- sleep hygiene

- stress reduction

obesity surgery

gastric sleeve: creates a smaller stomach

gastric bypass: creates a pouch stomach + bypasses the duodenum

how does stress contribute to obesity?

chronic stress → prolonged cortisol release →

activation of sympathetic NS → change in energy homeostasis → increased fat mass → higher BMI

how does insufficient sleep contribute to obesity?

sleep deprivation:

- ↑ ghrelin ↓ leptin → overeating → ↑ energy intake

- ↑ hedonic signaling → overeating → ↑ energy intake

- ↓ physical activity due to fatigue → ↓ energy expenditure

adult physical activity

- 150+ minutes per week of moderate - vigorous aerobic activity

- muscle strengthening at least 2 days per week

evidence based dieting strategies

1. calorie deficit

2. front load calories in the day (big breakfast, small dinner)

3. adequate fiber

- be sure that patient will adhere to whatever diet changes are put in place

overall treatment approach to obesity

- physical activity: 150 mins/week

- diet: any eating pattern suitable for the patient

- behavioral therapy

- AOMs: for BMI ≥27 + comorbidity OR BMI ≥30

- surgery: for BMI ≥35 comorbidity OR BMI ≥40

FDA approved pharmacotherapies for obesity

- phentermine mono therapy

- orlistat

- phentermine/ topiramate ER

- naltrexone/ bupropion SR

- liraglutide

- semaglutide

- tirzepatide

- setmelanotide

all FDA approved AOMs work by reducing appetite except...

orlistat (Alli)

works by reducing fat absorption