unit 4 Diabetes- ILE 1

most diabetics are

type 2

If you have a patient has auto antibodies they are

type 1 diabetic

is change in diet and physical activity a treatment option for T1D?

no

Causes for T1D

pancreatic Beta cells are being destroyed by the immune system via activated cytotoxic t-lymphocytes, macrophages, cytokines

-islet cells can also develop antibodies against insulin

-viruses can lead to this and so can environmental toxins (ex: early exposure to dairy)

T1D are unable to produce insulin and this causes hyperglycemia, why are T2D hyperglycemic?

insulin resistance, excessive hepatic glucose production, slow progressive beta-cell failure, reduced incretin effect, elevated renal tubular glucose reabsorption

pathology of T1D

apoptosis of beta-cells initiaties leukocyte and macrophage invasion of islet cells → termination of production of insulin in islet cells

beta-cells

cell in islet of pancreas that produces insulin

alpha-cells

cell in islet of pancreas that produces glucagon

delta-cells

cell in islet of pancreas that produces somatostatin

insulin molecule

consists of an A & B amino acid chain, binds Zn forming hexamers (inactive) that can form large crystalline arrays that prompt condensation and aggregation of hormone in the acidic core (this can be inhibited by c-peptide); when it precipitates into a dimer, it can signal the body to uptake glucose

tyroserine kinase receptor

insulin receptor composed of 2 alpha-chains that are extracellular and house insulin bonding domains & 2 beta-chains that penetrate through plasma membrane

when insulin combines with alpha subunits is causes the beta-chains to autophosphorylate and activate catalytic activity of the receptor

Diabetic keto acidosis (DKA)

caused by a high blood glucose and inadequate intracellular glucose for energy production → fat breakdown → release of fatty acids and ketones → ketones accumulate → blood acidosis

symptoms- fatigue, confusion, passing out, frequent urination, blurred vision, thirst, high blood sugar

Diabetic nephropathy

occurs 2 ways

1) diffuse when glomerular basement membrane thickens OR

2) Nodular deposition of albumin and other proteins in tubules and glomeruli

leads to… microalbuminuria (small amount of albumin in blood make it to urine) → macroalbuminuria

Diabetic cardiomyopathy

lipid accumulation in heart and causes changes to the shape

glycohemoglobin (Hb)

results from am irreversible reaction between glucose and hemoglobin, used in measuring A1C

A1C

measures how much glucose is actually bound to hemoglobin A (aka what % of hemoglobin proteins are glycinated)

When to diagnose diabetes?

random plasma glucose > 200mg/dL & fasting glucose >126 mg/dL on two separate occasions

Goals of diabetes management

FBG 80-130 mg/dL & PPBG <180mg/dL & A1C <7%

Endogenous insulin

body releases it to match BG rise

CSI

continuous subQ insulin infusion

MDI

multiple daily injections

Bolus

short acting insulin that can replicate insulin burst by pancreas and prevent glycemic excursions by carbs

Basal

long acting insulin and replicate continuous release by pancreas when fasting

What insulin is used in pumps?

bolus

When calculating insulin, what dosing range should be used?

0.4 - 1 U/kg/day

insulin carbohydrate level

500/TDD = # grams of carbs 1U bolus insulin will cover

insulin sensitivity factor (ISF)

1800/TDD = how much (#mg/dL) 1U will lower BG

Humalin R (regular insulin)

rapid acting (basal)

Afrezza (Inhaled insulin)

rapid acting

Novalog, Fiasp (Insulin Aspart)

rapid acting

Apidra (insulin Gluisine)

rapid acting

Admelog, Humalog (insulin lispro)

rapid acting

Humalin N (NPH)

intermediate acting

Levemir (insulin detemir)

long acting

Lantus, Basaglar, Toujeo (insulin Glargine)

long acting

Tresiba (insulin Degludec)

ultra-long acting

PZI insulin

protamine-zinc-insulin complex, less readily absorbed from body tissue, long acting

How is Tresiba so long lasting?

it has a glutamic acid linker and fatty acid side chain

Novo Nordisc

long-lasing insulin primarily used in T2D as it has a special fatty acid chain that reversibly binds to albumin

Drug class of metformin

biguanides

Metformin MOA

• lowers hepatic gluconeogenesis by liver → decreased glucose in circulation

• lowers intestinal absorption of glucose → decreased glucose in circulation

• increases insulin sensitivity → increased peripheral glucose uptake and utilization

• stimulated glucose transporter activity → facilitates glucose transport across membranes (does not produce hypoglycemia)

Advantages of Metformin

lowers FBG and A1C, no weight gain, no increased plasma insulin (no hyperglycemia), persistent efficacy, positive changes in plasma lipid profiles, decreased BP, helps prevent insulin dependance in T2D

Metformin ADRs

metallic taste, diarrhea, n/v, anorexia, and other GI symptoms

decreased absorption of B12 and folic acid

Contraindications of metformin

alcoholism, liver disease, renal disease, eGFR <30, CHF or CV, chronic cardiopulmonary disease

Glupose-dependent insulinotropic polypeptide (GIP)

T2D maintain the same concentration of this, bit its insulinotropic action is blunted; increases endogenous glucose-dependent insulin secretion by pancreas

Glucagon-like-peptide 1 (GLP-1)

concentration is reduced by half in T2D & it is rapidly broken down by the enzyme DPP-4

-increases engenous glucose-dependent insulin secretion from the pancreas

-increases uptake of glucose into tissues (ex: adipose tissue)

-decreases gastric emptying

-decreases glucose-dependent glucagon secretion

-increases satiety and fullness

MOA of GLP-1

G-protein receptors → induce intracellular signalling (cAMP PKA) → activate or prime insulin granules via calcium for secretion

• increase glycolysis → increased ATP/ADP ratio → increased insulin secretion

• decreased potassium channels and induces Ca+ mediated insulin secretion

GLP-1 RAs advantages

no hypoglycemia, weight reduction, decreases PPG excursions, decreases some CVD risk factors

GLP-1 RAs disadvantages

GI side effects, acute pancreatitis, thyroid tumors (do NOT use if history of thyroid cancer), increased HR, anti-exenatide antibodies

Trulicity (Dulaglutide)

GLP-1 RA

Byetta (Exenatide)

GLP-1 RA

Victoza, Saxenda (Liraglutide)

GLP-1 RA

Ozempic (Semaglutide)

GLP-1 RA

DPP-4

serine protease that is expressed on surface of endothelial cells (T lymphocytes), breaks down GLP-1 & GIP, so in T2D you want to inhibit this

SNAC technology for oral meds

formation of a less-acidinc ‘buffer zone’ directly around a tablet that prevents it from being broken by digestive enzymes and allows it to attach to lipid membrane of stomach lining, allowing drug molecules to move across cell barrier and into blood stream

Mounjaro & Zepbound (tirzepatide)

GIP & GLP-1 RA combo drug

MOA of tirzepatide

stimulates insulin secretion, lowers glucagon, slows digestion, lowers A1C, decreases appetite

SGLT2

reasorbes ~90% of glucose to recenter circulation

SGLT2 inhibitors advantages

increase insulin sensitivity in muscle and liver, decreased gluconeogenesis, improved Beta cell function, allows for insulin independence, weight loss, lower risk of hypoglycemia, decreased BP, decreases left ventricular mass

cons of SGLT2 inhibitors

polyuria, electrolyte imbalances, bacterial UTIs, Fungal genital infections, Malignancies breast and bladder, ketoacidosis

AKI

acute kidney injury

ASCVD

atheroscerotic cardiovascular disease (plaque build up in arteries)

Invokana (Canagliflozin)

SGLT2 inhibitor

Farxiga (Dapagliflozin)

SGLT2 inhibitor

Jardiance (Emplagliflozin)

SGLT2 inhibitor

contraindications of SGLT2 inhibitors

eGFR <20 & hold 3-4 days prior to surgery

if a patient has ASCVD what should be your first line T2D treatment be?

GLP-1 RA

if a patient has indicators of high CVD risk what should be your first line T2D treatment be?

SGLT2

if a patient has HF what should be your first line T2D treatment be?

SGLT2 &/or GIP/GLP-1 Ra (or just GLP-1 RA)

if a patient has CKD what should be your first line T2D treatment be?

SGLT2 OR GLP-1 RA

What has very high efficacy for weight loss?

semaglutide and tirzepatide

What has high efficacy for weight loss?

Dulaglutide and liraglutide

What has intermediate efficacy for weight loss?

GLP-1 RA

What has neutral efficacy for weight loss?

metformin and DPP-4i

What has a very high efficacy for glucose lowering in T2DM patients?

Dulaglutide, semaglutide, tirzepatide, insulin combo (ex GLP-1 RA and insulin)

What has a high efficacy for glucose lowering in T2DM patients?

GLP-1 RA, metformin, pioglitazone, SGLT2i, sulfonylurea, DPP-4i

What is the primary pic for weight management in T2D?

tirzepatide

what is the primary pick for T2Ds to lower A1C?

metformin

MASLD

accumulation of fat in the liver