Diabetes

carbohydrate digestion

starts in the mouth via salivary amylase (polysach-> shorter chain)

also small intestine via pancreatic amylase (short chain-> disach)

alpha-glycosidases

in the brush border of the small intestine (where villi are)

change disach to monosach (mainly glucose)

apical membrane

points towards lumen

basolateral membrane

points towards blood

SGLT1

Na+/glucose cotransporter across apical membrane

GLUT5

glucose, galactose, fructose, passive transporter across apical membrane

GLUT2

facilitated diffusion across basolateral membrane into intestinal fluid, then capillaries, followed by hepatic portal vein

GLUT1

glucose transporter expressed by many cells through basolateral membrane

Monosaccharides

are only able to be absorbed

proximal tubule

glucose and amino acid reabsorption

glycogenesis

glucose to glycogen (for storage)

glycogenolysis

glygen to glucose

gluconeogenesis

amino acid to glucose

glycolysis

glucose to 2 ATP + 2 pyruvate

lipogenesis

glucose to triglycerides

hyperglycemia

high blood sugar

pancreas releases insulin, transforming glucose into glycogen and glucose uptake(from blood to cells) from food

hypoglycemia

low blood sugar

pancreas releases glucagon, which transforms glygen into glucose

Beta cells in pancreas

release insulin and amylin

alpha cells

release glucagon

delta cells

release somatostatin

amylin

reduces glucose absorption from GI, inhibits gastric emptying, suppresses glucagon, supresses hunger

glucagon can perform

glycogenolysis or gluconeogenesis

C-peptides

are release 1:1 with insulin, so they can tell us insulin levels

insulin production in Beta Cells

Preproinsulin is made in ER, and proinsulin is processed in the Golgi to make insulin

incretins

GI hormones released after eatng

GLP-1 and GIP

GLP-1 and GIP

promote insulin secretion and slow down gastric emptying

DPP-4

degrades incretins

insulin effects in liver

inc glycogenesis

prevents glycogenolysis, gluconeogenesis, ketogenesis

insulin effects in muscle

inc glycogenesis, glucose oxidation, protein synthesis

insulin effects in adipose/fat tissue

inc lipogenesis

prevents lipolysis

insulin elimination

60:40 liver:kidney for endogenous

in diabetics 40:60 liver:kidneys for exogenous

Diabetes Mellitus

elevated glucose with little to no pancreas insulin secretion

T1DM

autoimmune

destruction of beta cells

T2DM

insulin resistance

Gestational DM

during pregnancy

alpha-glucosidase inhibitors

Oral

inhibits disacch and monosacch digestion

alpha-glucosidase inhibitor brand name generic

generic: acarbose brand name: precose

generic: Miglitol brand name: glyset

Amylin Analog

Subcut

reduces postprandial (after eating) glucose absorption

Box warning: severe hypoglycemia

DDI: concomitant oral drugs

Amylin Analog brand name generic

generic: pramlintide brand name: SymlinPen

Bile Acid Sequestrant

Oral

lowers LDL by making liver produce more bile acids

improves glycemic control in T2DM

Bile Acid Sequestrant brand name generic

generic: Colesevelam brand: Welchol

SGLT-2 Inhibitor

Oral

blocks SGLT-2 in proximal convoluted tubule reducing glucose reabsorption in kidney

DDI: UGT inducers inc metabolism of SGLY-2 inhibitors

SGLT-2 inhibitors brand name generic

generic: bexaglifozin brand name: brenzavvy

generic: ertugliflozin brand name: steglatro

generic: canagliflozin brand name: invokana

generic: dapaglifozin brand name: farxiga

generic: empaglifozin brand name: jardiance

SGLT-2 black box

ketoacidosis, lower limb amputation, volume depletion, hypoglycemia, necrotizing fasciitis, intravascular volume contraction

SGLT-2 inhibitors that improve cardio and renal outcomes

Empa, cana, dapa

SGLT-2 approved for HF with reduced ejection fraction

Dapa, Empa

SGLT-2 Inhibitors metabolism

glucuronidation

They are UGTs (which is why UGT inducers increase metabolism)

Anti-autoimmune medication

IV infusion

MOA: monoclonal antibody that deactivate T-cells by targeting CD3 (on t-cells)

Anti-autoimmune brand name generic

Teplizumab

Insulin replacement

MOA: exogenous insulin that replaces endogenous

AE: hypoglycemia

Rapid-acting insulin replacement drugs

Insulin lispro

insulin aspart

insulin glulisine

inhaled insulin

Rapid-acting insulin replacement onset and peak

within 20 min

within 3 hours

Short-acting insulin drugs

Regular insulin

short-acting insulin onset and peaks

within 60 min

within 3 hours

intermediate-acting drugs

NPH

intermediate-acting onset and peak

within 4 hours

within 8 hours

ultra-long/ long acting drugs

long acting:

insulin glargine

insulin detemir

ultra-long acting:

insulin degludec

ulta-long/ long acting onset and peak

within 8 hours

up to 48 hours

insulin replacement route of administration

subcutaneous, other than inhaled insulin

regular insulin can also be IVed

rapid insulins can also be infusions

Sulfonureas

Oral

beta cells may lose function

AE: hypoglycemia, CV mortality

sulfonurea DDI

alcohol, sulfa drugs, thiazides, rifampicin

Sulfonurea brand name generic

generic: glyburide brand name: glynase

generic: glipizide brand name: glucotrol

generic: Glimepiride brand name: amaryl

Sulfonylurean metabolism

Glimepride: CYP2C9

Meglitinides and sulfonurea MOA

inhibit SUR1 to block Katp potassium channel promoting insulin release from beta cells (need functioning beta cells)

Meglitinides

Oral

AE: hypoglycemic

Meglinitides DDI

Repa- concomitant gemfibrozil, clopidogrel, cyclosporin, CYP2C8 and 3A4 inducers/inhibitor

Meglinitides metabolism

repa: CYP2C8 and 3A4

Biguanides

oral

MOA:lowers blood sugar by decreating hepatic gluconeogenesis, also decreases intestinal glucose absorption and increases glucose tolreance

Black box: lactic acidosis

Biguanide brand name generic

generic: Metformin brand name: glucophage

Tiazolidinediones

Oral

MOA: increase insulin sensitivity (reduce resistance) by activating PPARy nuclear receptors

Black box: congestive HF

Tiazolidinediones DDI

Strong CYP2C8 inhitors or substrates

Tiazolidinediones metabolism

CYP2C8 substrates

Tiazolidinediones brand name generic

generic: Pioglitazone brand name: actos

GLP-1 receptor agonists

MOA: mimic GLP-1 to activate receptors (resist DPP4)

black box: thyroid C-cell tumors (seen in rodents)

GLP-1 receptor agonists DDI

drugs taken at same time (gastric emptying

GLP-1 receptor agonist metabolism

proteolytic cleavage

GLP-1 receptor agonists route

all subcut except semaglutide Rebylsus

GLP-1 receptor agonists bioavailability

dulaglutide: 50-65%

liraglutide: 55%

Semaglutide (ozempic): 89%

Semaglutide (rybelsus): 0.4-1%

GIP/GLP-1 receptor dual agonist

subcut

MOA: mimic GIP and GLP-1 to activate receptors (resist DPP-4)

Black box: thyroid C-cell tumors (in rodents)

AE: hypoglycemia

GIP/GLP-1 receptor dual agonist DDI

drugs taken at the same time

GIP/GLP-1 receptor dual agonist brand name generic

generic: tirzepatide brand name: Mounjaro

GIP/GLP-1 receptor dual agonist metabolism

proteolytic cleavage

DPP-4 inhibitors

Oral

MOA: reduce degradation of incretins and inhibits glucagon release

AE: hypoglycemia

DPP-4 DDI

saxagliptin with CYP3A4/5 strong inducers or inhibitors

DPP-4 inhibitor metabolism

Sax: CYP3A4/5 substrate

DPP-4 brand name generics

generic: saxagliptin brand name: onglyza

generic: sitagliptin brand name: januvia

generic: Alogliptin brand name: nesina

generic: linagliptin brand name: tradjenta

T2DM risk factors

genetic, non-white, HTN, HDL under 35 or total over 250

PCOS, CVD, GDM (gestational)

Hyperglycemia signs and symptoms

glucosuria, weight loss, infections, sexual disfunction

T1DM symptoms

Polydipsia, polyuria, polyphagia, and weight loss

T2DM symptoms

often asymptomatic

nocturia, polydipsia, polyuria

T1DM screening

antibody based for presymptomatic T1D

T2DM screening

over 35

overweight+ 1 risk factor

if normal do every 3 years

To diagnos t2DM a patient must present

2 abnormal tests at same time or different times, if hyperglycemia is not totally evident

Nonpregnant adults and children T2DM Diagnostic test results

FBG≥126mg/dL

BG≥200mg/dL

75 gram oral glucose test within 2 hr BG≥200mg/dL

A1c≥6.5%

Biguanide dosing

IR 1000mg BID

XR 2000mg 1x daily

with meals. titrate dose

(2000mg is maintenance dose)

Biguanide dosing adjustment

eGFR 30-45mL/min/1.73m^2: start slower at 500mg BID with renal monitoring

Biguanide contraindications

Acute/chronic metabolic acidosis

eGFR under 30mL/min/1.73m^2 (need good kidneys)

Biguanide warnings

Lactic acidosis (black box)

Vitamin B12 deficiency

Biguanide adverse effects

nausea diahreaa

Glycemic status assessment

should be checking up 2x/year

if goals arent being met (worsening or changes in health) meet every 3 months