Diabetes Mellitus Part II

diabetes definition

excessive excretion of urine

diabetes mellitus defined

disorder of carbohydrate, fat, and protein metabolism with absolute or relative insulin deficiency

Normal plasma glucose level

<6

E source brain solely relies on

glucose

Acute vs chronic complications of diabetes

Acute: Triggered by illness and factors related to plasma glucose level management (noncompliance with diet or pharm therapy or SEs of pharm therapy)

Chronic: Hyperglycemia affects cells that do not effectively reduce transport of glucose into the cell in a hyperglycemic state > intracellular hyperglycemia

Examples of acute complications in diabetes (3)

Hypoglycemia

Diabetic Ketoacidosis (DKA)

Hyperosmolar hyperglycemic syndrome (HHS)

Examples of chronic diabetes complications (7)

Microvascular:

• Retinopathy

• Neuropathy

• Nephropathy

Macrovascular

• Cerebrovascular disease

• PVD

• CAD

Other – e.g., infections

Cells vulnerable to chronic hyperglycemia (4)

capillary endothelial cells of retina, mesangial cells of renal glomerulus, neurons and schwann cells of peripheral nerves

(think microvascular complications)

Hypoglycemia defined by what 3 factors

1. development of neurogenic/autonomic or neuroglycopenic symptoms

2. below normal BG (<4 for diabetics with insulin treatment)

3. symptoms respond to admin of carbohydrate

Neurogenic vs neuroglycopenic symptoms

Neurogenic caused or mediated by NS

Neuroglycopenic shortage of glucose for NS

In hypoglycemia, what system is activated, leads to these (7) symptoms

SNS activation > trembling, palpitations, sweat, anxiety, hunger, nausea, tingling

In hypoglycemia what happens with the brain, causes what (8) symptoms

Abrupt glucose cessation to brain > difficulty concentrating, confusion, weakness, drowsiness, vision changes, difficulty speaking, headache, dizziness

In general, hypoglycemia occurs when BG vs someone with insulin treatment

2.5-3.3

If insulin treatment: <4

Hypoglycemia can be caused by exogenous, endogenous, or functional mechanisms, which is most common?

Diabetes pts exogenous mechanism of drug-induced hypoglycemia

Fear of hypoglycemia - negative social and emotional impact may make pts

reluctant to intensify pharm therapy

Examples of short-term risks vs long-term risks of hypoglycemia

Short-term risks: safety related (i.e. if they were driving or operating machinery). Prolonged coma can be associated with transient neuro symptoms like paresis, convulsions, encephalopathy

Long-term risks: mild intellectual impairment and rarely permanent like hemiparesis and pontine dysfunction

Describe key rule of severity of hypoglycemia and describe level 1, level 2, and level 3 hypoglycemia

NOT strictly defined by glucose levels

Level 1: autonomic symptoms, able to self-treat

Level 2: neuroglycopenic symptoms, +/-autonomic symptoms, able to self-treat

Level 3: unable to self-treat, requires assistance, unconsciousness may occur

2 causes of hypoglycemia and describe each

1. Relative excess of insulin in blood

From too much exogenous insulin or when insulin secretagogues like sulfonylureas are used

2. Deficits in glucose counter-regulation (particularly important in T1D)

Glucagon and epinephrine released during hypoglycemia become defective, which blunts otherwise autonomic symptoms associated with level 1 or 2 hypoglycemia and puts these pts at greater risk for level 3 hypoglycemia

Is hypoglycemia more common in T1D or T2, what does this effect

More common in T1D and occurs in >90% of individuals with T1D and often limits disease management

Can hypoglycemia occur in T2D?

Hypoglycemia can occur in T2D usually in those taking insulin secretagogues or using exogenous insulin

Risk factors for hypoglycemia (9)

exercise, alcohol, older age, renal dysfunction, infection, error in insulin dose, medication changes, cognitive dysfunction, mental health issues

Specific risk factors for severe hypoglycemia in T1D (8)

prior episode of severe hypoglycemia

current low hemoglobin-A1C (<6%)

impaired awareness of hypoglycemia (IAH)

long duration of diabetes

autonomic neuropathy

low economic status

adolescence

pre-school children unable to detect and/or treat mild hypoglycemia on their own

Hypoglycemia often triggered by

relative excess of insulin > BS decrease

First line of defense against hypoglycemia

decrease in endogenous insulin secretion

Normal functioning beta cells in hypoglycemia

suppress insulin when glucose drops to ~4.6

hypoglycemia > activation of what system, via _____ which stimulates _______ to release

SNS via hypothalamus, adrenal gland, counterregulatory hormones (epinephrine and NE)

What other system in hypoglycemia related to stress response

Hypothalamic-pituitary-adrenal axis > cortisol release

Role of liver in sympathoadrenal response to hypoglycemia (2)

1. Portal vein role in sensing hypoglycemia and activating counterregulatory response

2. Glucagon stimulates glycogenolysis and gluconeogenesis in liver

Glucagon released by ____________ in response to ___ stimulation and/or ___________

pancreatic alpha cells

SNS

BG levels too low

Counterregulatory hormones in hypoglycemia (4) cause what (2)

NE, epi, growth hormone, cortisol

> increase in glucose production, decrease glucose uptake in periphery (specifically adipose and m. tissues)

Neuroglycopenic symptoms occur due to

abrupt cessation of glucose delivery to the brain

level 1-2 conscious hypoglycemia treatment, effect

15g glucose or sucrose, produce 2.1 BG increase within 20 mins

level 3 conscious hypoglycemia treatment, effect

20g carbohydrate, helps increase BG by 3.6 within 45 mins (predicated on individual being able to swallow

Conscious person hypoglycemia treatment retest when, next steps?

Re-test BG in 15 mins and retreat with another 15 or 20g of carbohydrate if BG still <4

Treatment options (2) for hypoglycemia in unconscious person >5yo

No IV access 1 mg glucagon subcut or IM, or 3mg glucagon intranasally

IV access IV glucose 10-25g (20-50cc D50W) over 1-3 mins

what options equal 15 g of carbohydrate (5)

glucose tables, 3 tsps or 3 packets of table sugar in water, 175mL of juice or soft drink, 6 lifesavers, 1 tblsp of honey

Which type of sugar is preferred for hypoglycemia treatment and why, what is the exception and what should be used instead

monosaccharides like glucose because they are absorbed directly into the BS

If a pt is taking an alpha-glucosidase inhibitor, dextrose not sucrose should be used to treat hypoglycemia

When glycogen stores are depleted, ________ is ineffective

glucagon

Glucagon will not be as effective in those who (2)

have consumed more than two standard alcoholic drinks within previous few hours or those with advanced liver disease

_________ glucagon has shown faster dosing and more complete dosing compared to ____ glucagon and may be admin by non-medically trained

intranasal, IM

caution with intranasal glucagon

in those with T2DM on insulin secretagogues

DKA and HHS are

life threatening hyperglycemic emergencies associated with significant morbidity and mortality

DKA and HHS should be suspected in those who

have diabetes and are ill

Hyperglycemic conditions associated with diabetes (DKA/HHS) from (2) which > increase in ________ >

insulin deficiency and some form of trigger > counterregulatory hormones > hyperglycemia

in hyperglycemic emergencies, _________ imbalances occur due to (2)

Electrolyte imbalances occur due to metabolic acidosis and/or osmotic diuresis

Most serious electrolyte imbalances in hyperglycemia, why

hypo and hyper kalemia due to associated risk for cardiac arrhythmias

Hyperglycemia emergencies can lead to adverse ________ sequelae, (3)

neurological sequelae (permanent complications): cerebral edema, coma, death

Diabetic Ketoacidosis (DKA) vs Hyperglycemic Hyperosmolar Syndrome (HHS) (driven by, which more common, acid imbalance and pH, mortality, glucose level, clinical features

Diabetic Ketoacidosis (DKA)

• Driven by absolute insulin deficiency (common in T1D)

• More common

• Lower mortality (4-10%)

• Glucose >14

• Metabolic acidosis (pH ≤7.3 and bicarbonate decrease of 15 or less)

• Clinical fts: acetone breath (fruity odor), kussmaul respiration (due to metabolic acidosis)

Hyperglycemic Hyperosmolar Syndrome (HHS)

• Driven by relative insulin deficiency (common in T2D)

• Less common

• Higher mortality (10-50%) large range due to underlying illnesses

• Glucose >34 (plasma glucose much higher)

• Metabolic acidosis due to ketoacidosis less likely to occur, pH usually normal

• ECFV depletion (hypovolemia) more severe (osmolality ≥320) HHS dx marker

hyperglycemic emergencies (DKA/HHS) counterregulatory hormones including glucagon are _________, glucagon directly does what in liver

increased, stimulates glycogenolysis

hyperglycemic emergencies (DKA/HHS) counterregulatory hormones cause

decreased glucose uptake in peripheral tissues

hyperglycemic emergencies (DKA/HHS) impact on protein

Protein breaks down to provide amino acids to liver for gluconeogenesis

What else breaks down in hyperglycemic emergencies (DKA/HHS), why (relative vs absolute insulin deficiency)

adipose

to form glycerol for gluconeogenesis (if there is relative insulin deficiency) and free fatty acids to form ketones in liver (in case of absolute insulin deficiency)

What causes metabolic acidosis in hyperglycemic emergencies

Specific ketones formed: beta-hydroxybutyric acid and acetoacetic acid

what 2 events drive hyperglycemia in hyperglycemic emergencies (DKA/HHS)

Glycogenolysis and gluconeogenesis

hyperglycemia in hyperglycemic emergencies (DKA/HHS) leads to ___________ which > __________

Hyperglycemia > osmotic diuresis > large electrolyte loss in urine

Total body deficit of water in adults usually about how much in DKA and how much in HHS

5-7L in DKA

7-12L in HHS (representing loss of 10-15% of body wt)

If untreated, fluid loss in hyperglycemic emergencies can lead to

circulatory failure

Hyperosmolality and metabolic acidosis can cause (2)

CNS depression and coma

development of DKA or HHS depends on

if there is relative or absolute insulin deficiency

Should DKA be ruled out if someone has a normal BG?

NO

in certain conditions, such as pregnancy or with SGLT2 inhibitor use

SGLT2 inhibitors use lowers threshold for developing DKA

List 7 management strategies of DKA and HHS

Fluid rehydration

Correction of hyperglycemia

Resolution of ketoacidosis

NaHCO3

Monitor and correct electrolytes (especially K+)

Diagnosis and treatment of coexisting illness

Monitor for and prevent complications specifically adverse neurological sequelae (i.e. cerebral edema)

Why is fluid rehydration used in DKA and HHS management

restore normal ECFV and tissue perfusion

Resolution of ketoacidosis usually occurs with

insulin therapy and fluid rehydration

NaHCO3 management of DKA and HHS for what and not in what population

for severe metabolic acidosis (not in pediatrics)

Is K always added to DKA and HHS maintenance fluid? Why?

• K added to maintenance fluid even if K levels not low because when metabolic acidosis begins to correct, K will shift back into cell > extracellular/serum levels to decline

  • Since there is already overall depletion of K, due to K having moved out of the cell during metabolic acidosis and loss of K via osmotic diuresis, it is important to anticipate to avoid arrhythmias

A sudden change in ECF osmolality can occur if? > _______

hyperglycemia corrected to quick > cerebral edema

Cerebral edema more common in (2)

DKA and in children

_% of all acute care hospital admissions related to diabetes or its complications

10

__% of ppl with diabetes will die of a heart attack or stroke

80

__% ppl with diabetes have CKD and CKD+diabetes is leading cause of kidney failure

50

most common cause of blindness in ppl ≤65yo

diabetes caused

__/10 non-traumatic limb amputations due to diabetes

7

____________ is first clinical sign of diabetes in up to 12% of males

Erectile dysfunction

List the theories of pathogenesis for chronic complications (5)

polyol pathway, formation of advanced glycation end products (AGE’s), protein kinase C (PKC), increased hexosamine pathway activity, oxidative stress

What is the polyol pathway in general

Alternative metabolic pathway for tissues not requiring insulin for glucose uptake/transport

tissues in polyol pathway (5)

kidney, RBCs, BVs, eye lens, nerves

Polyol pathway- aldose reductase normally does what VS when hyperglycemia

Normally converts toxic aldehydes > inactive alcohols with hyperglycemia glucose shunted to pathway > aldose reductase converts glucose > sorbitol

Polyol pathway NADPH is, which has what effect

consumed (decreased)

normally an essential cofactor for regenerating glutathione which is a critical intracellular antioxidant 

decreased NADPH: Increases susceptibility of cell to intracellular oxidative stress

polyol pathway what happens to sorbitol

slowly converted to fructose

polyol pathway- Sorbitol + Fructose  accumulation >

increase in intracellular osmotic P > attracts water > cell injury

polyol pathway- key part of what changes in diabetics

visual changes and cataracts

polyol pathway - sorbitol interferes with _____ in ___, damages ________ cells, and disrupts __ conduction

ion pumps in nerves, damages schwann cells, and disrupts n. conduction

polyol pathway - what happens to RBCs which causes what

Swollen RBCs can become stiff and perfusion in microcirculation can become compromised

recurrent hyperglycemia increases formation of _____________ products through nonreversible binding of glucose to (3)

advanced glycation end products (AGEs)

proteins, lipids, nucleic acids

Hyperglycemia increases advanced end glycation products in (2) in (3)

collagen and other proteins

in RBCs, BV walls, interstitial tissues

Explain AGE and RAGE

Advanced glycation end (AGE) products + their receptors (RAGE) have properties that can > tissue injury or associated diabetes conditions

Effects of AGE/RAGE (8)

modification of intracellular proteins specifically those involved in gene transcription

cross-linking and trapping of proteins

thickening of basement membrane

increased permeability of BVs

damage to nerves

stimulation of cellular proliferation (inducing lipid oxidation, oxidative stress, and inflammation)

diminished endothelial function with less NO synthesis and loss of vasodilation

promotion of platelet adhesion and reduced fibrinolysis

one example of advanced glycation end product, explain

glycated hemoglobin A1C (HbA1c)

When serum glucose interacts with N-terminus of beta chains of hemoglobin

Glycation of hgb interrupts ability to achieve optimal conformation affecting its function (i.e. reducing affinity for O2 and increasing ROS production)

Protein kinase C (PKC) activated by what, regulates (4)

Intracellular hyperglycemia increases diacylglycerol (DAG) which activates PKC

Regulate permeability, vasodilator release, endothelial activation, growth factor signalling

Consequences of Elevated DAG & PKC (5)

• BF abnormals due to decreased endothelial NO synthase (vasodilator), increased endothelin-1 (vasoconstrictor)

• Increased vascular permeability and angiogenesis due to increased vascular endothelial growth factor

• Capillary and vascular occlusion due to increased collagen fibronectin and decreased fibrinolysis respectively

• Pro-inflamm gene expression

• Increased ROS and disordered mitochondrial function > oxidative stress

Activation of PKC in BVs > associated disease of (3)

retina, kidney, nerves

hexosamine pathway describe

Chronic hyperglycemia  > shunting of excess intracellular glucose into the hexosamine pathway  O-linked  glycosylation of proteins > alteration in signal transduction pathways and oxidative stress

O-linked attachment of N-acetylglucosamine on serine and threonine residues of transcription factors > pathologic changes in gene expression associated with insulin resistance and CV complications

oxidative stress is a significant component of what pathways (4)

AGE/RAGE, polyol, PKC, and hexosamine pathways

oxidative stress occurs when

production of ROS outweighs body’s antioxidant defense mechanisms

what two main factors contribute to ROS production

Chronic hyperglycemia and mitochondrial dysfunction

What does ROS damage? what does this cause?

cellular components (proteins, lipids, DNA) > disrupting normal physiological processes

Oxidative stress negatively impacts normal functioning of cells contributing to (2)

beta-cell dysfunction and insulin resistance

Oxidative stress contributes to chronic complications of diabetes by

damaging BVs and impairing endothelial function > retinopathy, nephropathy, CV diseases, etc.

oxidative stress can also trigger _________, further impairing function of tissues and organs

inflammation

Microvascular diabetic complications are leading cause of (3)

blindness, end stage renal disease and neuropathies