15-16: Pharmacology of Glucose & Insulin

Lispro/Aspart

Rapid insulin

Exogenous

MOA

• Similar to regular insulin, but dissociates quickly into monomer

• Forms weak hexamers → dissociates quickly

NOTES

• Rapid onset 10-30 min, short duration (4 hours)

• Mimics prandial (mealtime) release of insulin

AE

• Hypoglycemia, weight gain

Regular Insulin

Short acting insulin

Exogenous

Administered:

• SubQ

• IV (emergencies)

  • preferred

MOA

• Binds insulin R (TK activity) → increases glucose uptake

• Structurally similar to endogenous insulin + Zn ion → hexamer stability

• Forms strong hexamers → slower monomer dissociation → delayed absorption

NOTES

• Onset ~30 min, duration 6-8 hrs (longest of prandial insulins)

• Must give ~30 min before meals

• Acts as prandial bolus insulin (mimics normal post-meal insulin release)

AE

• Hypoglycemia, weight gain

Glargine

Detemir

Long acting insulin

Exogenous

MOA

• Slower onset than NPH, duration ~24 hrs

NOTES

• Low risk of hypoglycemic episodes

AE

• Hypoglycemia, weight gain

CI

• Glargine & detemir should NOT be mixed in same syringe

NPH
Intermediate acting insulin

Exogenous

Administered:

• SubQ

MOA

• Regular insulin + Zn + protamine

• Protamine delays absorption (must be cleaved off before insulin can be absorbed)

NOTES

• Delayed absorption = intermediate onset (2-4 hrs)

• Long duration: 12–18 hrs

• Higher risk of hypoglycemia (unpredictable peaks)

USE

• Basal control (morning and/or bedtime)

• Often combined with rapid or short-acting insulin for mealtime spikes

AE

• Hypoglycemia, weight gain

Chlorpropamide (1st gen)

Glipizide

Glyburide

Sulfonyureas (SFUs)

MOA

• Inhibits K channel → b-cell depolarizes → Ca influx → insulin release

• Metabolized by liver, excreted in urine/feces

NOTES

• Duration = 12-24 hrs

• Must eat on time 

AE

• 1st gen → dilsulfiram-like effects 

• Hypoglycemia, weight gain, SIADH with chlorpropamide

CI

• In hepatic + renal failure → impaired clearance → hypoglycemia

Repaglinide

Increases endogenous insulin

Administered:

• Oral

MOA

• Inhibits K channel → b-cell depolarizes → Ca influx → insulin release

NOTES

• Rapid onset, taken with meals (skip meal → skip dose)

• Only effective if patient has functioning pancreas (NOT for T1D)

• Stimulate endogenous insulin release, so C-peptide increases

AE

• Hypoglycemia (increases with renal failure), weight gain

Metformin

Increase tissue sensitivity to insulin

MOA

• 1° = Decrease hepatic glucose production → normalizes FBG

• 2° = Increases insulin-mediated peripheral glucose uptake 

• Metformin → AMPA-PK → reduce hepatic glucose production → lower blood glucose

NOTES

• 100% excreted by kidneys

• Does NOT promote insulin secretion → NO hypoglycemia + weight gain

USE

• Initial drug → in most T2D (especially in obese/insulin resistant patients)

• Alone or in combination with other oral drugs/insulin

• Lowers FBG more than prandial glucose

• Off label → treats PCOS

ADV

• No weight gain, cheap, beneficial effect on lipids, NO hypoglycemia as monotherapy (but increases risk with insulin/other hypoglycemics)

AE

• Mild GI distress, B12 deficiency

• Lactic acidosis (rare) → risk increases with CHF, renal failure, hepatic dysfunction, alcohol abuse, sepsis

  • Reduce dose in half if GFR < 45 ml/min

  • STOP drug if GFR < 30 ml/min

CI 

• Diabetic ketoacidosis; acute/chronic metabolic acidosis 

• Renal failure (GFR < 30 ml/min)

• CHF due to increased risk of lactic acidosis

Pioglitazone

PPARy agonist

MOA

• 1° = Increases peripheral sensitivity to insulin

• Enhance insulin sensitivity to target tissues

• Increases expression of GLUT4

NOTES

• Does NOT promote insulin secretion

• PPARy found in → adipose, skeletal m., b-cells, vascular endothelium, macs, CNS

AE

• Weight gain (insulin sensitivity → fat accumulation)

• Increased ECF volume (increased ENaC → edema)

• Hepatotoxicity, risk of bone fracture in elderly 

CI

• CHF due to ability to increase ECF volume → makes HF worse

ADV

• Improves HDL cholesterol & plasma TGs; LDL neutral

• No hypoglycemia as monotherapy

DISADV

• 6+ weeks for maximum effect

Acarbose

a-glucosidase inhibitor

MOA

• Reversible a-glucosidase enzyme inhibitor

• Decreases digestion of complex carbs → lowers post-prandial blood glucose

NOTES

• Taken at beginning of meals

USE

• Mono/adjunct therapy in hyperglycemia management

• Most useful in hyperglycemia

ADV

• Monotherapy → NO hypoglycemia

• No weight gain

• Skip meal, skip dose

AE

• GI → flatulence, bloating, abdominal discomfort, diarrhea 

CI

• IBD, colonic ulceration, intestinal obstruction (anyone with GI issues)

DI

• Use glucose for hypoglycemia (sucrose inhibited by a-glucosidase enzyme inhibitors)

Exenatide

GLP-1 receptor agonist

MOA

• Increases post-prandial insulin release

• Suppress glucagon release 

  • Decreases blood glucose 

NOTES

• Injected subQ 2x daily, 1 hr before meals

USE

• Adjunct therapy in T2D

  • Patients with inadequate blood glucose control with metformin

AE

• Nausea, vomiting, risk of pancreatitis

CI

• Gastroparesis (from delayed gastric emptying)

ADV

• Promotes b-cell proliferation (but can lead to pancreatitis)

• Slow gastric emptying time → decreased appetite → weight loss

DISADV

• Injectable (subQ), expensive, not combined with insulin

DI

• DPP-IV inhibitors (risk of pancreatitis)

***Think about OZEMPIC!!!

Sitagliptin

Dipeptidyl peptidase IV (DPP-4) inhibitors

MOA 

• Inhibits DPP-4 enzyme (DPP-4 usually degrades GLP-1 + GIP)

  • Increases circulating endogenous GLP-1

  • → Increases insulin concentration + decreases glucagon

  • → Decreases blood glucose

USE

• T2D (monotherapy or combination)

  • Combination → with Metformin, SFUs, TZD, insulin

AE

• FDA warning: increased risk of HF (previous history of HF, renal disease)

• Delayed gastric emptying 

• Risk of pancreatitis 

• Joint pain (degradation of NP-Y)

CI

• In renal failure (accumulation of drug)

ADV

• Weight neutral, monotherapy → no hypoglycemia, given orally

DISADV

• Expensive, SFUs + DPP-4 → risk of hypoglycemia

Canaglifozin

Dapaglifozin

SGLT-2 inhibitors

MOA

• Independent insulin secretion & insulin action

  • Decreases reabsorption of glucose in PCT (blocks SGLT)

  • Increases urinary excretion of glucose → decreases blood glucose

USE

• T2D

AE 

• Hypovolemia/hypotension (due to increased urination, thirst)

• Hyperkalemia 

• GU infection 

• Increases hepatic glucose production

ADV

• Weight loss, given orally

DISADV

• Expensive

CI 

• In renal failure (GFR < 30 ml/min, accumulation of drug)

Amylin Analogues

MOA

• Slows gastric emptying

• Reduces postprandial glucagon & glucose release & promotes satiety

USE

• Taken before meals

• Adjunct to insulin therapy in T1D & T2D

AE

• Hypoglycemia (with insulin), nausea

ADV

• Modest weight loss

DISADV

• SubQ injections 

DI 

• Reduce mealtime insulin dose (50% to avoid hypoglycemia)

• Do not mix with insulin in the same syringe

Glucagon

Hypoglycemia management

MOA 

• Acts on liver to increase blood glucose through multiple metabolic pathways 

  • Increases glycogen phosphorylase, decreases glycogen synthase

USE

• Beta blocker OD → counteract effects of b-blocker toxicity

• Severe hypoglycemia → treat unconscious patients with severe hypoglycemia

Octreotide

Long-acting somatostatin analogue

Hypoglycemia management

MOA 

• Blocks release of insulin & glucagon

USE

• Insulinomas, glucagonomas, thyrotropin-secreting pituitary adenoma

Diazoxide

Hypoglycemia management

MOA

• Opens K channels → b-cells hyperpolarize → decreased Ca influx → decrease insulin release

USE 

• Insulinomas

• SFUs OD

AE

• Opens K channels in smooth/cardiac m. → cells hyperpolarize → vasodilation

  • → Hypotension