ENDO 1 - Main points

What are the consequences of short-term hyperglycemia and thier MOAs?

Symptoms of early diabetes (more common in T1DM → destruction of pancreas)

1) Polyuria (excess urination)

• Hyperglycemia = large glomerular filtration load of glucose = saturation of SGLT transporters in the proximal tubule 

  • SGLT2: Normally responsible for 90% of the reabsorption of glucose 

  • SGLT1: Contributes more (up to 50%) when glucose load increases

    • 1) Even with this extra help, the transporters cannot reabsorb all the filtered glucose → remains in tubular fluid + acts as an osmotic diuretic → retains water in the tubule = increased urine production

2) Polydipsia (increased thirst)

• Polyuria leads to dehydration +  low BP → thirst → increased drinking

• Increased drinking is a compensatory response to volume loss from polyuria.

3) Weight loss + polyphagia (increased hunger)

• Loss of insulin function (T1DM) → Inability to store glucose + increase glucose loss in urine = low energy stores + weight loss + poor glucose utilization (despite having high glucose concentrations in the blood)

  • Bad glucose utilization = increased hunger and polyphagia

  • Depletion of energy stores = weight loss

Explain the mechanism of early kidney nephropathy in patients with hyperglycemia. What medications help this effect?

Early: RAAS based

Late: Vasoconstriction and age/rage process

• Saturation of SGLT transporters = increased reabsorption of glucose + Na + Cl (paracellularly) → decreased Na/Cl sensed by the macula densa = activation of tubuloglomerular feedback, leading to an INCREASE in GFR (increases filtration pressure) to “defend” perceived low GFR → renal damage in diabetes!

  • Hyperfiltration

  • Podocyte damage

  • Protein in urine

• SGLT blockers indirectly help (because they allow more Na/Cl to travel to macula densa), inhibit the tubuloglomerular feedback, decrease glomerular filtration pressure, and decrease RAAS!

What is the blood glucose concentrations at which polyuria develops?

Typically quite high (above 250 mg/dl) in an otherwise healthy kidney

What is ketosis?

• Ketosis (alternative fuel utilization)

  • With inadequate insulin function, the body utilizes fatty acids for the metabolism/production of ketone bodies = ketosis 

What is AGE and RAGE? What are they caused by and what do they lead to?

Hyperglycemic cellular injury = consequence of chronic hyperglycemia

Advanced glycation end products (AGE)

• Produced through non-enzymatic attachment of glucose (or other monoglycerides) to proteins, followed by chemical modification of the glucose to form a reactive terminal group

• Effect of the reactive terminal group:

  • 1) Direct damage: Cross-linking proteins

    • Alteration in normal protein structure + function =

    • Damages/changes vascular proteins →  endothelial cell damage + loss of capillaries

  • 2) Activation of the receptor for advanced glycation end-products (RAGE)

    • RAGE - transmembrane protein is found on many cells (i.e., endothelial cells in blood vessels, immune cells, smooth muscle cells, kidney cells, neurons)

    • When bound to AGE leads to:

      • Increased production of ROS (oxidative damage)

      • Increased production of inflammatory mediators 

      • Increased production of extracellular matrix (ECM) proteins = Basement membrane thickening (a preventative attempt to restrict bacterial infection)

      • Increased expression of RAGE

      • Decreased synthesis of nitric oxide (NO) + Increased synthesis of endothelin = vasoconstriction

      • Apoptosis (programmed cell death) of endothelial cells = loss of capillaries

      • Increased platelet and RBC aggregation microthrombosis

  • 3) Oxidative damage

  • 4) Inflammatory damage

What is an example of a glycated protein? What is it used for and what is the difference between this and an AGE?

• Hemoglobin A1c is a glycated protein → it is not an AGE (does not undergo chemical modification) 

  • Good representation of your glucose levels over 120 days (lifespan of RBCs)

Explain the mechanism of AGE/RAGE/long-term hyperglycemia’s effect in late-stage kidney nephropathy.

Early: RAAS based

Late: Vasoconstriction and age/rage process

• RAGE activation leads to:

  • Decreased synthesis of nitric oxide (NO) + Increased synthesis of endothelin = vasoconstriction → hypoperfusion of glomeruli = glomerular ischemia → death

  • Increased production of extracellular matrix (ECM) proteins = Basement membrane thickening → prevent bacterium from coming in

  • Mesangial cell (tissue macrophages) increase → try to keep the bowman’s space clean but since they are part of the immune response = inflammatory response + damage to endothelial cells leading to…

  • Apoptosis of endothelial cells = loss of glomerular capillaries → decrease GFR

Explain the mechanism of how AGE/RAGE/long-term hyperglycemia affects nerves. What does it lead to?

• Neuropathy (damage to the nerves outside your brain and spinal cord)

  • AGE/RAGE vascular damage → damage/blockage of vessels supplying nerves → inadequate blood supply → nerve infarcts → nerve damage → loss of sensation → limb injury → gangrene

Explain the mechanism of how AGE/RAGE/long-term hyperglycemia affects a patient’s eyes. What does it lead to?

• Retinopathy

  • Damaged retinal vessels (microinfarctions) → bleeding

  • Vascular occlusion/ischemia → axonal swelling → cotton-wool spots

  • Leaky damaged capillaries → hard exudates

  • Ischemia → compensatory vascular proliferation/new vessel formation

    • Some parts of the eye are not receiving blood so the blood vessels that are still okay will proliferate

    • Can lead to blindness

Explain the mechanism of how AGE/RAGE/long-term hyperglycemia affects a patient’s vascular system (macrovascular disease). What conditions is this like? What medication does this process warrent?

• AGE-RAGE → endothelial damage → lipid deposition in the subendothelium

• Diabetes-associated dyslipidemia → inflammatory system activation  → atherosclerosis → CAD/PVD

  • Same MOA as HTN and dyslipidemia but different origin

    • Explains why if patient is diabetic and has NORMAL LDL levels they still need a statin

Explain the mechanism of how AGE/RAGE/long-term hyperglycemia affects a patient’s liver. What conditions is this like? What medication does this process warrent?

• Dyslipidemia

• Non-alcoholic faatty liver disease:

  • Decreased/loss of insulin function = 

    • Increased lipolysis

    • Increased fuel delivery to liver (too much fuels in liver)

    • Increased triglyceride synthesis

    • Fatty acid oxidation

      • Increased fat storage in hepatocytes = fat accumulation in liver (contributing to Non-alcoholic fatty liver disease)

Where is insulin released from? Where does it bind? What/where are its effects? What stimulates it?

• Insulin

  • Released from beta cells (hepatocytes) → binds to insulin receptors on cell surfaces  = conformational change → phosphorylation → intracellular messenger/signaling pathways = metabolic effect

  • Anabolic (build/store) effect:

    • Pancreas: Inhibits glucagon release

    • Hepatocytes: activates pathways of fuel storage (glycogen synthesis + lipogenesis), inhibits pathways of fuel mobilization (gluconeogenesis)

      • Glycogen synthesis:

        • Decrease glucose levels in liver = increase glucose transport into liver (GLUT2) = decreased glucose levels in bloodstream

    • Skeletal muscle: ↑ glucose uptake through GLUT4, ↑ glycogen synthesis, ↑ and protein synthesis

    • Adipocytes: ↑ glucose uptake through GLUT4, ↑ triglyceride synthesis, ↓ and triglyceride breakdown/lipolysis

  • Stimulus: rising BG, fed state (0-4 hours after a meal) → helps to decrease BG towards normal

Where is glucagon released from? Where does it bind? What/where are its effects? What stimulates it?

• Released from alpha cells → binds to GPCR on cell surfaces

• Catabolic effect (breakdown):

  • Hepatocytes:

    • Glycogenolysis: 

      • Conversion of glycogen to glucose = increased glucose in liver = glucose travels down gradient (in GLUT2) into blood stream

    • Gluconeogenesis

• Stimulus: Falling BG, fasting state (more than 4 hours after meal) → helps to increase BG towards normal

What is the difference between fed and fasting states in terms of the main fuels source and over goal?

• Fed (0-4 hours after meal)

  • Increased insulin

  • Main fuel source = exogenous fuel from meal (glucose)

    • Skeletal muscle: glucose used for ATP, excess glucose stored as glycogen

    • Liver: glucose used for ATP, excess glucose stored as glycogen

    • Adipocytes: glucose used for ATP, excess glucose and fatty acids stored as triglycerides

  • Goal: Use and store fuel

• Fasting (>4 hours after meal)

  • Increased glucagon and counter-regulatory hormones (I.e., epinephrine, cortisol) → mobilize fuel

  • Main fuel source = stored endogenous fuel (shift towards fatty acids)

    • Stored fuels (glycogen, TG) broken down, glucose and fatty acids released from other tissues → most cells use fatty acids for energy

      • Skeletal:

        • Glycogen broken down, glucose used for ATP

        • Fatty acids taken up for ATP as well

      • Liver:

        • Glycogen broken down, glucose released

        • Fatty acids take up from bloodstream for ATP

      • Adipocytes - TG broken down, fatty acids used for ATP and released

  • Goal: Mobilize fuel and maintain BG

What is the main purpose of the TCA cycle?

To take acetyl coA derived from fuels → use its energy through byproducts (NADH, and FADH2) which are used in oxidative phosphorylation (where most ATP is produced) 

• Major input (acetyl-CoA) → Major outputs (3 NADH, 1 FADH2, 1 GTP, 2 CO2)

What are the irreversible steps within the TCA cycle? What are the rate limiting aspects of this cycle?

Irreversible steps:

1) Citrate synthesis (acetyl coA → citrate)

2) Isocitrate dehydrogenase (isocitrate → alpha-ketoglutarate)

3) alpha-ketoglutarate dehydrogenase  (alpha-ketoglutarate → succinyl coA)

• Thiamine pyrophosphate (vit B1 required)

Rate limiting aspects:

• Substrate availability → cycle needs substrates like acetyl coA

• Product inhibition → accumulation of products slows pathway

  • Regulated steps slow when ATP and NADH are elevated

Explain the ATP and electron transport coupling chain

Connected through a proton gradient across the inner mitochondrial membrane

1) NADH → Complex I and FADH₂ → Complex II donate electrons.

2) Electrons travel:

• Complex I/II → CoQ → Complex III → cytochrome c → Complex IV

• Complexes I, III, and IV pump H⁺ from the mitochondrial matrix into the intermembrane space.

• Complex II does NOT pump H⁺.

3) At Complex IV, O₂ is the final electron acceptor and combines with electrons + H⁺ → H₂O.

4) H⁺ accumulation in the intermembrane space creates an electrochemical gradient = potential energy.

5) H⁺ flows back into the matrix through ATP synthase (Complex V) → energy drives ADP + Pi → ATP.

• Complex I = 4 H⁺

• Complex III = 4 H⁺

• Complex IV = 2 H⁺

Compare uncouplers of oxidative phosphorylation vs direct electron transport chain inhibitors vs ATP synthase inhibitors.

• Uncouplers of oxidative phosphorylation

  • Allows H to cross the inner mitochondrial membrane without going through ATP synthase (out)

  • Electron transport continues but ATP synthesis decreases/stops →

    • ETC can continue running rapidly in an attempt to restore ATP synthesis = released as heat + speeds up oxygen consumption

• Direct electron transport chain inhibitors

  • Direct electron transport chain inhibitors: prevent ETC from generating proton gradient

    • Stops whole process whereas the uncouplers allow ETC to continue but stop ATP synthesis

• ATP synthase inhibitors

  • ATP synthase blocked → H cannot return through ATP synthase → ATP synthesis stops = build up of H gradient to the point where ETC eventually stops (loss of both ATP synthesis and ETC)

What happens during fatty acid oxidation, where does it happen, and how is it regulated?

• TG → Fatty acids→ beta-oxidation (in mitochondria) → acetyl coA and NADH and FADH2

  • Acetyl-CoA → TCA cycle → ATP

  • NADH and FADH2 feed into the oxidative phosphorylation to generate ATP

• Long chain fatty acids (chunky)

  • Long-chain fatty acid → carnitine shuttle → mitochondrial matrix → β-oxidation → acetyl-CoA + NADH + FADH2

• Regulation of Fatty acid oxidation

  • Fed/high insulin → ↓ mitochondrial FA entry → ↓ β-oxidation

  • Fasting/low insulin → ↑ FA availability/entry → ↑ β-oxidation

What is glycolysis, where does it occur, what are the irreversible steps, and how is it regulated?

• Glucose → pyruvate + ATP + NADH

  • Pyruvate: Can be converted into acetyl coA by pyruvate dehydrogenase (PDH)

  • Occurs in cytosol (does not require mitochondria) → all cells can perform glycolysis, including RBCs, which do not have mitochondria.

• 3 irreversible steps:

  • 1) Hexokinase/glucokinase (HK/GK)

    • Glucose → glucose-6-phosphate 

  • 2) Phosphofructokinase (PFK) 

    • Major regulated step within glycolysis 

  • 3) Pyruvate kinase (PK) 

    • Final irreversible step producing pyruvate

• Regulation:

  • High ATP → inhibits PFK and PK → ↓ glycolysis

  • Fed/high Insulin → ↑ glucokinase (GK) and PFK activity → ↑ glycolysis

How do glycolysis/PDH and β-oxidation change between fed and fasting states?

FED = burn glucose

• ↑ Insulin

• ↑ Glycolysis

  • ↑ pyruvate dehydrogenase (PDH) activity

• ↓ β-oxidation

• Glucose → pyruvate → acetyl-CoA → TCA

FASTING = burn fat

• ↓ Insulin

• ↓ Glycolysis/PDH

• ↑ β-oxidation

• FA → acetyl-CoA + NADH + FADH₂ → ATP

What are the major fuel sources for ATP, and what fuels do RBCs and the brain use?

• Glucose

  • Glucose → glycolysis → pyruvate → acetyl-CoA → TCA → NADH/FADH₂ → OXPHOS → ATP

• Fatty acids

  • FA → β-oxidation (mitochondria)→ acetyl-CoA + NADH/FADH₂ → TCA/OXPHOS → ATP

• Ketone bodies

  • Ketones → acetyl-CoA → TCA/OXPHOS (mitochondria)→ ATP

• RBCs = glucose ONLY

  • No mitochondria

  • Cannot do TCA, β-oxidation, or OXPHOS

  • ATP comes from glycolysis only

• Brain

  • Normal/fed: primarily glucose

  • Does not significantly use fatty acids

  • Prolonged fasting: increasingly uses ketone bodies to spare glucose

How does the body prevent hypoglycemia during fasting?

• ↓ Blood glucose → ↓ insulin + ↑ counterregulatory hormones
  (glucagon, catecholamines, cortisol, GH)

• Response:

  • 1) Increase glucose availability

    • Glycogenolysis: liver glycogen → glucose, especially early fasting

    • Gluconeogenesis: makes new glucose, increasingly important with prolonged fasting

  • 2) Decrease the body's need for glucose (use of other fuels)

    • ↓ Insulin + ↑ catecholamines → activation of hormone-sensitvie lipase (HSL) = lipolysis + ketogenesis

    • Adipose TG → free fatty acids + glycerol

      • Free fatty acids → β-oxidation → acetyl CoA

      • Glycerol → liver → gluconeogenesis

      
      

    • Ketogenesis → alternative fuel that uses acetyl CoA, especially for the brain during prolonged fasting

      • Note: Lipolysis can happen without ketogenesis, while ketogenesis cannot happen without lipolysis.

Explain the mechanism of action for insulin release from beta cells.

• Increased blood glucose → enters through GLUT2 → glucose undergoes glycolysis = increased ATP → ATP-sensitive K channels close = decreased K leaving the cell → increased membrane depolarization 

• Because of the depolarization voltage gated Ca2+ channels open → Ca influx into the Beta cells → triggers insulin-containing vesicles to undergo exocytosis → insulin enters the blood

Explain the mechanism of how glucagon is released from alpha cells.

• Low glucose → less enters alpha cells thorugh GLUT1 → less glucolysis → ATP levels fall → ATP-sensitive K channels stay open (K efflux continues) → decreased membrane depolarization

• Ca/Na channels open → Ca influx into the Alpha cells → triggers glucagon-containing vesicles to undergo exocytosis → glucagon enters the blood

What is gluconeogenesis? What are the major carbon sources for gluconeogenesis?

Gluconeogenesis (GNG) = synthesis of glucose from non-carbohydrate precursors

• 1) Lactate → pyruvate → glucose

• 2) Glycerol → gluconeogenic intermediates → glucose

• 3) Glucogenic amino acids (especially alanine) → pyruvate/TCA intermediates → glucose

  • Protein is a major source of carbon for gluconeogenesis during fasting

Explain the energy requirements for gluconeogenesis and where it comes from. What are the processes that regulate GNG?

• GNG is energy-expensive and requires ATP, GTP, and NADH. 

  • β-oxidation of fatty acids is critical for providing the energy needed to drive gluconeogenesis.

    • TG → Fatty acids and glycerol → fatty acids go through beta-oxidation (in mitochondria) to produce Acetyl-CoA and NADH and FADH2

      • Acetyl-CoA → TCA cycle → ATP

    • lactate/glycerol/amino acids → gluconeogenesis → glucose

• Regulation

  • 1) Fasting/counterregulatory hormones → ↑ GNG

    • Glucagon + catecholamines + cortisol → activate key GNG enzymes

  • 2) Fed state/insulin → ↓ GNG

  • 3) ↑ β-oxidation → ↑ acetyl-CoA + energy

    • Acetyl-CoA activates pyruvate carboxylase, while β-oxidation supplies the large amount of energy required for GNG.

What is the difference between glycogenesis and glycogenolysis? What are their effects in the liver and muscle?

• Glycogenesis = glucose storage as glycogen

  • Fed  → insulin stimulates

  • Regulation in liver vs muscle

    • Liver: increased blood glucose → hepatocyte through GLUT2→ glucose-6-Phosphate → glucose-1-Phosphate → glycogen

    • Muscle: increased Insulin → GLUT4 moves to membrane → ↑ glucose uptake from blood → glucose → glucose-6-phosphate (enzyme hexokinase) → glycogen utilization and storage

• Glycogenolysis = glycogen breakdown

  • Fasting/exercise → counterregulatory hormones/glucagon stimulate

  • Regulation in liver vs muscle

    • Liver: releasing glucose into the bloodstream

      • Glycogen → G1P → G6P —(glucose-6-phosphatase)→ glucose

    • Muscle: Provides glucose-6-phosphate for glycolysis

      • G6P → F6P → glycolysis → ATP for muscle contraction (personal reserve for that muscle)

Explain the transportation of glucose through different organs (Brain, RBCs, skeletal muscles, adipose, liver, kidney). What are they each independantly dependant on?

GLUT transporters: facilitated diffusion → down concentration gradients

• Brain - GLUT3, RBCs - GLUT1 

  • Glucose uptake is not insulin-dependent

• Skeletal muscle and adipose: GLUT4

  • Insulin dependent

  • After a meal: ↑ Blood glucose → ↑ insulin → ↑ GLUT4-mediated glucose uptake into muscle/adipose

  • During fasting: ↓ insulin → ↓ GLUT4-mediated glucose uptake

  • Exercise → ↑ GLUT4-mediated glucose uptake independently of insulin

• Liver: GLUT2

  • Not insulin dependent

  • GLUT2 is bidirectional

  • Fed: Blood glucose → GLUT2 → hepatocyte

  • Fasting state: Glycogenolysis + gluconeogenesis → G6P → glucose

• Kidney/intestines: SGLTs

  • sodium-glucose cotransporters (SGLTs) → uses the Na⁺ concentration gradient to move glucose into cells

What happens to glucose when it enters most cells? Why does this happen

• Once glucose enters most cells, it is phosphorylated:

  • Glucose → glucose-6-phosphate (G6P)

    • This helps maintain a low concentration of free intracellular glucose, favoring continued glucose movement from the blood into the cell.

What does a CGM measure? Which patients could benefit from use of a CGM?

• CGM

  • Measures glucose in interstitial fluid (may have delay in readings/not accurate readings under 100mg/dL)

  • Use fingerstick when CGM reading doesn't match symptoms or is unreliable

Patients using insulin, T1DM, T2DM using insulin, frequent hypoglycemia, pregnant individuals

How is insulin made in pancreatic beta cells? How is it stored?

• Preproinsulin (scaffold peptide) → Proinsulin (A chain, B chain, and C-peptides) is cleaved → Insulin + C-peptide (biomarker of endogenous insulin production)

  • A chain and B chains are held together by disulfides

• Insulin is stored as hexamer crystals

  • Composed of 2 zinc and 6 insulin

  • This allows β cells to store insulin until a stimulus, primarily increased blood glucose, triggers secretion.

How is endogenous vs exogenous insulin cleared?

• Endogenous:

  • Liver: ~60%

  • Kidney: ~40%

• Exogenous:

  • Kidney: ~60%

  • Liver: ~40%

What happens if insulin levels are too high?

• Hypoglycemia

  • → palpitations, tachycardia, tremor, hunger

  • → severe: confusion, weakness, seizure, coma if untreated

• Hypoglycemic unawareness

  • Higher risk after frequent hypoglycemia

    • Confusion

    • Weakness

    • Seizures

    • Coma

What happens if insulin levels are too low?

• Liver cells turn fatty acids into ketones

  • Ketones: alternative fuel source (bs no glucose in cell for energy)

    • Need insulin to uptake glucose into the cell

  • Ketones are acidic and can drop the pH of the blood

  • If left uncorrected, high ketone levels can lead to diabetic ketoacidosis (DKA), → life threatening condition

Other than low/high insulin, what are other AE’s that can ocur with use of insulin?

• Immunopathology

  • Insulin allergy (rare with human insulin)

  • Immune insulin resistance (common) 

    • Limited inactivation of insulin by IgG antibodies

• Lipodystrophy/hypertrophy at the injection site

  • Dystrophy with older animal insulin

  • Hypertrophy with human (change sites/liposuction)

What is Exogenous glucagon used for? What does it depend on? What routes of administration exists for it?

• Hypoglycemic emergencies

  • Particularly when the patient is unconscious/altered and cannot safely take oral glucose, and IV glucose is not possible or IV access is difficult.

  • Depends on the patient having hepatic glycogen stores

    • Glucagon → ↓ hepatic glycogen → ↓ glucose available for release → reduced glucagon response

  • Routes and formulations

    • SQ, IM injection, prefilled pen, Nasal spray (Baqsimi)

How does insulin aggregation affect its absorption and duration? What can aggregation be altered by?

• Insulin can aggregate: Monomers → dimers → hexamers (2 Zn + 6 insulin)

• More aggregation = more hexamers

  • Slower dissociation

  • Slower SC absoprtion

  • LONGER duration

• Less aggregation = less hexamers

  • Faster absorption

  • Faster onset

• Altering aggregation:

  • Low pH → more aggregation

  • Ions (Zinc) → more aggregation

How are lispro, aspart, and glulisine modified to produce rapid action?

Lispro

• Switches B28 Pro + B29 Lys → B28 Lys + B29 Pro

Aspart

• B28 Pro → Asp

Glulisine

• B3 Asn → Lys

• B29 Lys → Glu

• B chain on insulin (B28 - Pro, B29 - Lys, and B30 - Thr)  → help stabilize the overall dimer and hexamer structure

  • These changes affect dimer/hexamer stability → less aggregation but do not influence insulin binding to receptors

Compare and contrast T1DM and T2DM with regard to: the typical age of onset, body weight, the underlying pathophysiology of the hyperglycemia, predisposition to ketoacidosis, response to therapy: diet, exercise, insulin, and non-insulin glycemic agents.

• T1

  • Age of onset: Child/adolescence + any age

  • Body weight: Lean/normal weight

  • Underlying pathophysiology: Autoimmune destruction of pancreatic beta cells

  • Ketoacidosis: High predisposition

  • Response to therapy:

    • Diet/Exercise: Can be helpful for glucose management but cannot replace insulin

    • Insulin: Required for survival

    • Non-insulin glycemic agents: Not primary treatment → fundamental problem is lack of insulin

• T2

  • Age of onset: Adulthood + sometimes younger patients

  • Body weight: Overweight/obesity

  • Underlying pathophysiology: Insulin resistance + progressive β-cell dysfunction → relative insulin deficiency

  • Ketoacidosis: Much lower predisposition, through DKA can occur still

  • Response to therapy:

    • Diet/Exercise: Very important; lifestyle modification can improve insulin sensitivity and glucose control

    • Insulin: may eventually be needed, especially as beta cell function declines

    • Non-insulin glycemic agents: Major component of treatment 

      • Including medications that improve insulin sensitivity, decrease hepatic glucose production, increase insulin secretion, increase urinary glucose excretion, etc.

How do you calculate a patient estimated average glucose? (eAG) Why is this used?

eAG (mg/dL) ≈ 28.7 × A1C − 46.7

• EX: A1C = 7% = eAG of 154mg/dL

• ADAG trial (A1C-Derived Average Glucose study) demonstrated a strong relationship between A1C and a patient's average glucose.

What are the ambulatory glucose profile (AGP)/CGM goals for most adults with diabetes?

• Time below range (TBR) = Hypoglycemia

  • <70 mg/dL should be <4%

  • <54 mg/dL should be <1%

• Time in range (TIR) = 70-180mg/dL >70% of the time

• Time above range (TAR)  = Hyperglycemia

  • >180 mg/dL: <25%

  • >250 mg/dL: <5%

What are the general ADA glycemic goals for many nonpregnant adults with diabetes?

• A1C → <7% 

• Preprandial (pre-meal) glucose → 80–130 mg/dL 

• Postprandial glucose → <180 mg/dL 

• CGM Time in Range → >70% 

• Time Below Range <70 → <4% 

• Time Very Low <54 → <1%

What is diabetic ketoacidosis (DKA)?

• DKA: profound insulin deficiency (associated with T1DM)→ hyperglycemia + ketone production + metabolic acidosis