PHARM ENDO

An enzyme in the GI tract that converts complex starches and oligosaccharides to monosaccharides; inhibited by acarbose and miglitol

Alpha-glucosidase

Insulin-producing cells in the endocrine pancreas

Beta cells

Dangerously lowered serum glucose conc.; a potential toxic effect of high insulin concentrations and the secretagogue class of oral antidiabetic drugs

Hypoglycemia

Acidemia due to excess serum lactic acid; can results from excess production or decreased metabolism

Lactic acidosis

A form of chronic hyperglycemia caused by immunologic destruction of panccreatic beta cells

T1DM

A form of chronic hyperglycemia initially caused by resistance to insulin; often progresses to insulin deficiency

T2DM

What is the short-term storage form of glucose?

Glycogen

Where is glycogen stored?

Mainly in liver, also muscle

What is the breakdown of glycogen into glucose?

Glycogenolysis

What is the key process during fasting, exercise, or stress when the body needs rapid glucose?

Glycogenolysis

What is the synthesis of new glucose molecules?

Gluconeogenesis

Where does gluconeogenesis primarily occur?

Liver

What process helps keep blood glucose available for the brain and RBC?

Gluconeogenesis

What is the breakdown of glucose to pyruvate for ATP production?

Glycolysis

What are the peptide hormones produced in the pancreas?

• Insulin

• Glucagon

• Somatostatin

What cells produce insulin?

Beta cells

What cells produce glucagon?

Alpha cells

What cells produce somatostatin?

Delta cells

What hormone?:

• Synthesized as proinsulin

• Undergoes proteolytic cleavage

Insulin

What is insulin secretion controlled by?

• Blood glucose levels

• Amino acids

• Hormones

• Autonomic mediators

What is the physiology of insulin release?

• Glucose taken up into beta cells of pancreas through GLUT-2

• Phosphorylated by glucokinase, acting as a glucose sensory

• Products of glucose metabolism enter mitochondrial respiratory chain, generate ATP

• Rise in ATP causes K+ channel blockade → membrane depolarization → Calcium influx

• Inc. in intracellular calcium causes pulsatile insulin exocytosis

What are the results of the second messenger cascade from insulin binding?

• Peripheral insulin sensitivity

• B cell development

• Central leptin sensitivity

What transporter?:

• All tissues, especially RBC, brain

• Basal uptake of glucose; transport across the BBB

GLUT 1

What transporter?:

• Beta cells of pancreas; liver, kidney; gut

• Regulation of insulin release, other aspects of glucose homeostasis

GLUT 2

What transporter?:

• Brain, placenta

• Uptake into neurons, other tissues

GLUT 3

What transporter?:

• Muscle, adipose

• Insulin-mediated uptake of glucose from the blood

GLUT 4

What transporter?:

• Gut, kidney

• Absorption of fructose

GLUT 5

What enzymes have binding specificity with downstream molecules?

IRS-phosphorylated tyrosine kinases

What are the multiple effects of insulin’s second message system?

• Translocation of glucose transporters to the cell membrane

• Results in glucose uptake

• Inc. glycogen synthase activity; increase glycogen formation

• Effects on protein synthesis, lipolysis, lipogenesis

• Activates transcription factors enhancing DNA synthesis, cell growth, and division

Effects of insulin in the liver

• Inhibits glycogenolysis

• Stores glucose

• Stops making new glucose

Effects of insulin in the muscle

• Takes up glucose from the blood

• Increases glycogen synthesis and protein synthesis

Effects of insulin in adipose tissues

• Increases triglyceride storage

• Promotes glucose uptake and storage in adipocytes

  • Absorbed glucose is converted into triglycerides and stored for long-term energy

Physiology of glucagon secretion

During hypoglycemia, intracellular glucose levels fall along with glycolysis-generated ATP in the mitochondria → ATP sensitive potassium channels close → depolarization → calcium channels open with influx of calcium → glucagon secretion

What are the effects of glucagon?

• Hepatic glycogenolysis

• Activates gluconeogenesis

• Degrades triglycerides to fatty acids and glycerol

  • Glycerol enters gluconeogenesis

What condition?:

• Common among children, adolescents, young adults

• Destruction of beta cells

• Absolute deficiency of insulin

• Pancreas unable to respond to glucose

• Classic symptoms: polydipsia, polyphagia, polyuria, weight loss

T1DM

What condition?:

Treatment and Monitoring

• Insulin therapy to mimic endogenous secretion as closely as possible

• Goal of insulin therapy→ maintain normal blood glucose levels; avoid wide fluctuations in glucose

• Control hyperglycemia, avoid ketoacidosis, maintain adequate levels of glycosylated hemoglobin (HbA_1C)

• Glucometers

T1DM

What condition?:

• Lack of insulin sensitivity

• Some pancreatic beta-cell function

• Insufficient insulin secretion to maintain glucose homeostasis with presence of inc. peripheral insulin resistance

• Beta-cell mass possibly declines with time

• Obesity can lead to insulin resistance

T2DM

What condition?:

Treatment

• Goal: maintain normal blood glucose levels and prevent development of long-term complications

• Weight loss, exercise, dietary modifications

• Pharmacologic intervention

• With declining beta-cell function, insulin therapy often needed

T2DM

What condition?:

• Onset or first recognition during pregnancy

• Insulin is approved as treatment

• Metformin, glyburide used (off label use, not approved)

GDM

What can untreated diabetes lead to?

• Retinopathy

• Nephropathy

• Neuropathy

• Cerebrovascular complications

• CV complications

• Peripheral vascular disease

What medications?:

• Raise blood glucose levels → indicated for acute treatment of hypoglycemia

• Depending on product, raises glucose levels within ~5-15 minutes

• Uses:

  • Severe hypoglycemia → lifesaving

  • Endocrine diagnosis

  • Beta-receptor blocker overdose

  • Radiology of bowel

Glucagon preparations

What medications?:

• Do not require mixing prior to admin

• Gvoke HypoPen

• Gvoke PFS

Premixed injective glucagon solutions

What medication?:

• Baqsimi

Glucagon nasal powder

What medication?:

• SC admin

• Available in two doses: pediatrics and adults

  • Pediatric patients > 2 yo

• Injected directly on exposed skin (upper arm, lower stomach, outer thigh)

• AE: GI (N/V), injection site injections

• CI: hypersensitivity, insulinoma, pheochromocytoma

Gvoke HypoPen/PFS

What medication?:

• Glucagon nasal powder

• 3mg as one actuation into one nostril

• Treatment of severe hypoglycemia in people with diabetes > 1 yo

• CI: Patients with pheochromocytoma, insulinoma, hypersensitivity

Baqsimi nasal powder

What medication?:

• AE: N/V, HA, upper respiratory tract irritation, watery eyes, redness of eyes, itchy nose, throat, eyes, dysgeusia

• Warning/precautions:

  • Substantial inc. in BP in patients with pheochromocytoma

  • Hypoglycemia in patients with insulinoma

  • Hypersensitivity and allergic rxns

  • Lack of efficacy in patients with decreased hepatic glycogen

Baqsimi nasal powder

What medications increase the production of insulin so they are only effective for T2DM?

Insulin secretagogues

What medications?:

• MOA: Exogenous insulin replaces absent insulin secretion in T1DM or supplements insufficient insulin secretion in T2DM

• Pharmacokinetics:

  • Insulins preps vary in onset and duration of activity

  • Typically administered SC

  • Continuous SC insulin infusion (insulin pump)

  • For renal insufficiency → dose reduction may be necessary

Insulin and insulin analogs

What medications?:

• AE:

  • Hypoglycemia

  • Weight gain, injection site rxns, lipodystrophy

  • Inhaled insulin → potential for bronchospasm

Insulin and insulin analogs

What are the insulin delivery systems?

• Insulin vials, syringes

• Insulin pens

• Continuous subcutaneous insulin infusion devices

• Inhaled insulin

Prandial dosing

Around mealtime

What insulins are used in prandial dosing?

Rapid or short-acting

Longer-acting insulin given once or twice daily; flat or peakless

Basal

Shorter-acting insulins given more frequently (mealtimes); peaks

Bolus

Rapid acting insulin

• Lispro (Humalog)

• Aspart (Novolog)

• Glulisine (Apidra)

Short-acting insulin

• Regular insulin inj

• Inhaled regular insulin (Afrezza)

Intermediate-acting insulin

NPH insulin

Long-acting (peakless) insulin

• Insulin glargine (Lantus, Toujeo, Basaglar)

• Insulin degludec (Tresiba)

What medications?:

• All are clear solutions at neutral pH

• Mimic prandial insulin release; controls postprandial glucose

• Used when quick glucose correction is needed

• More rapid absorption, quicker onset, shorter duration of action

Rapid acting insulin

What medications?:

• Administered 15 mins preceding a meal or within 15-20 minutes after starting meal

• Used in external insulin pumps

• Treatment of uncomplicated diabetic ketoacidosis

Rapid acting insulin

What medications?:

• Hypoglycemic effects seen within 30 mins after SC admin

• Injected SC 30 mins before a meal

• Peak effects ~2 hours, last 5-7 hours in typical doses

• IV infusions used in diabetic ketoacidosis and during perioperative management of insulin-requiring diabetics

• Clear solution

Short acting insulin

What medication?:

• Humulin, Novolin

• Neutral protamine Hagedorn (NPH)

• Less soluble; results in delayed absorption and longer duration

• Used for basal (fasting) control in T1DM or T2DM

Intermediate acting insulin

What medications?:

• Usually given along with rapid or shorting acting insulin for mealtime control

• SC administration

• Cloudy suspension

• Onset ~2 to 5 hours; duration ~4 to 12 hours

Intermediate acting insulin

What medications?:

• Insulin glargine (Lantus, Toujeo, Basaglar)

• Insulin degludec (Tresiba)

• ONLY SC

Long acting insulin

What medications?:

• Flat, prolonged hypoglycemic effect with no peak

• Forms precipitate at inj site that releases insulin over period of time

• Onset to ~1 to 1.5 hours

• Max effect ~ 4 to 6 hrs; maintained for 11-24 hours or longer

• Typically dosed once a day

• Clear solution

Long acting insulin

What insulins’ formulations are acidic and should not be mixed with other insulins?

Long acting insulin

What medication?:

• Remains in solution at physiologic pH

• Slowly releases

• Longest half-life of long-acting insulin ~25 hours

• Onset ~30-90 minutes; duration >42 hours

• Typically once a day dosing

Insulin Degludec (Tresiba)

What can NPH (intermediate-acting) be mixed with?

• Short acting: regular insulin

• Rapid acting analogs: lispro (Humalog), aspart (Novolog)

What is the rule of thumb for combinations of insulin?

• NPH is “mixing partner”

• Clear before cloudy: draw up rapid/short acting first, then NPH to avoid contaminating vials

Humalog mix 75/25 or 50/50

Fixed ratio of insulin lispro protamine suspension (intermediate-acting) + insulin lispro (rapid acting)

• 75% lispro protamine sulfate, 25% lispro

• 50% lispro protamine sulfate, 50% lispro

What is the protein that is combined with lispro crystals that delays absorption?

Protamine

Novolog mix 70/30

70% insulin aspart protamine + 30% insulin aspart

Humulin 70/30, Novolin 70/30

70% NPH + 30% regular insulin

What medication?:

• Dry powder formulation of recombinant regular insulin

• Small, single-use device

• Peak levels ~12-15 minutes, declines to baseline in 3 hours

• Administered right before a meal; if needed, dependent on glucose levels, additional doses 1-2 hours after a meal

• Color coded cartridge:

  • 4 (blue), 8 (green), 12 (yellow)

Inhaled insulin (Afrezza)

What medication?:

• AE: cough, small drop in pulmonary function possible

• Boxed warning: Acute bronchospasm risk

• CI: Smokers and patient with chronic lung disease (ashtma, COPD)

• Spirometry prior to initiation of therapy

Inhaled insulin (Afrezza)

Stages of T1D

• Stage 1: T cells begin to attach beta cells

• Stage 2: Some beta cells destroyed → abnormal blood sugar; T cells continue to attack remaining beta cells

• Stage 3: Almost all beta cells destroyed → T1DM symptoms

What medication?:

• CD3-directed antibody

  • Prevents immune cells from attacking insulin-producing pancreatic beta cells

• Indication/Usage:

  • Delays onset of Stage 3 T1DM in adults and pediatric patients age > 8 yo at Stage 2 T1DM

Teplizumab

What should you do prior to initiating teplizumab?

• Confirm Stage 2

  • with at least 2 positive pancreatic islet autoantibodies in those who have dysglecmia without overt hyperglycemia using an oral glucose tolerance test

• For patients who meet criteria for Stage 2 T1DM, ensure clincal history does not suggest T2DM

• Obtain CBC and liver enzyme tests

What medication?:

• Dosage forms: 2mg/2mL single-dose vial

• Administered as IV infusion (over a minimum of 30 minutes) once daily for 14 days

• Warnings/Precautions:

  • Cytokine release syndrome (CRS): premedicate, monitor liver enzymes

  • Serious infections

  • Lymphopenia

  • Hypersensitivities

Teplizumab

Before initiation of teplizumab, in order to avoid cytokine release syndrome, how should you premedicate?

• Nonsteroidal or APAP

• Antihistamine, and/or

• Antiemetic before each dose for at least the first 5 days of the 14-day course

Vaccine requirements prior to initation of Teplizumab

• Administer live-attenuated vaccines at least 3 wks prior to treatment

• Administer inactivated or mRNA vaccines at least 2 wks prior to treatment

What medications?:

• Bind to sulfonylurea receptor to stimulate insulin secretion

• Sulfonylureas

• Meglitinides

Insulin secretagogues

What medications?:

• Act on liver, muscle, adipose tissue to dec. glucose levels

Metformin, thiazolidinediones (TZDs)

What medications?:

• Slow intestinal absorption of glucose

Alpha-glucosidase inhibitors

What medications?:

• Inhibit renal reabsorption of glucose

SGLT2 inhibitors

What medications?:

• Stimulate insulin release when bound to sulfonylurea receptor

• Sulfonylureas

• Nonsulfonylurea secretagogues

Insulin secretagogues

What are the sulfonylureas

• Glimepiride

• Glipizide

• Glyburide

What are the non-sulfonylureas secretagogues

• Nateglinide

• Rapaglinide

What medications?:

• Insulin secretagogues

• Bind to receptor (part of K+ channel) → inhibit potassium efflux → depolarization → voltage-gated calcium channel opens → influx of calcium → release of preformed insulin

• Primary action: stimulate insulin release from beta-cells

Sulfonylureas

What medication?:

• Sulfonylurea

• Cautious use in cardiovascular disease or eldery

• Taken with meals

• Contraindicated in hepatic impairment and renal insufficiency

Glyburide

What medication?:

• Sulfonylurea

• Taken 30 mins AC breakfst

• Hepatic metabolism; contraindicated in significant liver impairment

• Lower potency, shorter duration compared to glyburide; preferable in elderly and renal impairment

• Also available as ER prepration

• Available in combo with Metformin

Glipizide

What medication?:

• Lowest dosage of sulfonylureas

• Option in renal impairment and elderly

• Give with first main meal

Glimepiride

What medications?:

• AE:

  • Hypoglycemia, hyperinsulinemia, weight gain

  • Use with caution in hepatic or renal insufficiency or CI depending on impairment

    • Accumulation causing hypoglycemia

  • Renal impairment may inc. duration of action increasing risk of hypoglycemia with glyburide

Sulfonylureas

What sulfonylureas are safer choices with renal impairment and eldery?

Glipizide and glimepiride

Drugs that may reduce the effects of sulfonylureas, leading to loss of glucose control

• Atypical antipsychotics

• Corticosteroids

• Diuretics

• Niacin

• Phenothiazines

• Sympathomimetics

Drugs that may potentiate the effects of sulfonylureas, leading to hypoglycemia

• Azole antifungals

• Beta-blockers

• Chloramphenicol

• Clarithromycin

• Monoamine oxidase inhibitors

• Probenecid

• Salicylates

• Sulfonamides

What medications?:

• MOA: Insulin secretagogues; Close potassium channels in beta cells → increase insulin release

• Effects: Reduce circulating glucose in those people with beta cells

• Uses: T2DM

• PO active; duration of activity 10-24 hours

• Toxicity: hypoglycemia, weight gain

Sulfonylureas

What medication?:

• Stimulates insulin secretion

• Regulate potassium efflux which regulates beta-cell insulin release

• MOA similar to sulfonylureas; should not be used together

• Rapid onset, short duration

• Effective in early release of insulin seen after a meal → post prandial glucose regulators

• Before meals 0.25-4mg

Repaglinide

What medication?:

• AE:

  • Hypoglycemia

  • Weight gain

  • CI with gemfibrozil

    • Gemfibrozil inhibits hepatic metabolism of med → increases effects

  • Caution hepatic impairment

Repaglinide

What medication?:

• Binds to sulfonylurea receptor to stimulate insulin secretion

• Causes rapid, transient insulin release from beta cells by closing potassium channels

• Taken AC

• 60 and 120mg tablets

• Monotherapy or combo with non-secretagogue agents

• AE: hypoglycemia

• Safe in renal impairment and eldery

Nateglinide