Week 7: Diabetes Type 2

What is Type II diabetes?

Gradual loss of peripheral insulin sensitivity with beta-cell dysfunction, leading to hyperglycemia

What causes hyperglycemia in Type II diabetes?

Beta cells cannot produce/release enough insulin to overcome peripheral insulin resistance

Pathology in Type II diabetes:

Insulin resistance + beta-cell failure

Treatments for Type II diabetes:

Lifestyle changes, oral anti diabetic drugs, and sometimes insulin

What are the major Type II diabetes drug classes?

Insulin secretagogues, alpha-glucosidase inhibitors, biguanides, thiazolidinediones, incretin analogues/DPP-4 inhibitors, and insulin

What are the initial tx choice for Type II diabetes drugs?

Metformin and sulfonylureas

Hypoglycemic Type II diabetes drugs:

Sulfonylureas and meglitinides

Antihyperglycemic Type II diabetes drugs:

Alpha-glucosidase inhibitors, biguanides, and thiazolidinediones

Sulfonylureas:

Insulin secretagogues that block pancreatic ATP-sensitive K+ channels to stimulate insulin release

Examples of sulfonylureas:

Glimepiride, glipizide, glyburide, tolbutamide

Meglitinides:

Fast onset insulin secretagogues that block pancreatic K+ channels to stimulate insulin release

Examples of meglitinides:

Repaglinide and nateglinide

What happens when beta-cell K+ channels close?

Depolarization → voltage-gated Ca2+ channels open → insulin exocytosis

What are side effects of sulfonylureas and meglitinides?

Hypoglycemia, weight gain, and CYP450 drug interactions

What are incretins?

GI hormones released with food that enhance insulin secretion

Incretin =

INtestine seCREtion INsulin

Incretin analogues:

drugs that bind incretin receptors and mimic incretin action to increase insulin secretion

Examples of incretin analogues:

Exenatide, Trulicity, Ozempic, Wegovy, Victoza

What are beneficial effects of incretin receptor agonists?

Reduced gastric emptying, increased satiety, weight loss

What are adverse effects of incretin receptor agonists?

Nausea, possible pancreatitis risk, decreased appetite, dysgeusia, dyspepsia, xerostomia

DPP-4 inhibitors:

Block DPP-4 enzyme to increase activation of endogenous incretins

What are examples of a DPP-4 inhibitor?

Sitagliptin, alogliptin, saxagliptin, linagliptin

Acarbose:

Alpha-glucosidase inhibitor that acts locally in the GI tract to reduce monosaccharide formation

Alpha-glucosidase inhibitors:

slow digestion/absorption of glucose by preventing formation of easily absorbed monosaccharides

Examples of alpha-glucosidase inhibitors:

Acarbose and miglitol

What are side effects of alpha-glucosidase inhibitors?

Gastric distress, diarrhea, flatulence

Metformin:

Biguanide that decreases hepatic/renal gluconeogenesis and increases insulin sensitivity

Actions of metformin (MOA still unclear):

Decreases gluconeogenesis, decreases glucose absorption, decreases plasma glucagon levels, increases glycolysis

Other uses for metformin:

Pre-diabetes, anti-cancer, anti-aging, neuroprotection, long-COVID prophylaxis

What are side effects of metformin?

GI distress, possible weight loss, lactic acidosis risk, water retention (peripheral swelling)

Thiazolidinediones:

Insulin sensitizers that activate PPAR and insulin responsive genes

What are examples of thiazolidinediones?

Pioglitazone and rosiglitazone

PPAR:

Peroxisome proliferator activated receptor

What are side effects of thiazolidinediones?

Fluid retention, weight gain, increased fracture risk, possible bladder cancer risk

Inhaled insulin:

Afrezza

Less control than injection, acute bronchospasm risk, not tested in children

What should a diabetic patient do before a dental appt?

Eat a balanced meal within 2 hours and take medications as prescribed

What appt timing is preferred for diabetic patients?

Early morning appointments

What complications are caused by loss of insulin or insulin sensitivity?

Hyperglycemia causing neuropathy, cardiovascular disease, nephrotoxicity, retinopathy, and impaired wound healing

What Type II drug classes target beta-cell dysfunction?

Sulfonylureas, meglitinides, DPP-4 inhibitors, GLP-1 analogs

What Type II drug classes target hepatic glucose overproduction?

Metformin, thiazolidinediones, DPP-4 inhibitors, GLP-1 analogs

What Type II drug classes target muscle/fat insulin resistance?

Thiazolidinediones and metformin

What Type II drug classes target gut glucose absorption?

Alpha-glucosidase inhibitors, GLP-1 analogs, pramlintide

Oxidative stress in Type II diabetes:

Hyperglycemia and insulin resistance cause mitochondrial dysfunction and ROS production

Why are beta cells prone to oxidative stress?

Beta cells have low antioxidant enzyme levels

What pathways are activated by ROS in beta cells?

JNK, p38, and PKC

How does ROS reduce insulin gene expression?

it suppresses PDX-1 and MafA binding to the insulin gene promoter

How does oxidative stress impair insulin secretion?

Reduces mitochondrial respiratory chain proteins and ATP production

ER stress in Type II diabetes:

Hyperinsulinemia increases insulin transcription/translation, causing unfolded or misfolded protein buildup in the ER

UPR:

Unfolded protein response triggered by PERK, IRE1, and ATF6 to help protein folding/degradation

What happens when UPR cannot handle ER protein load?

ER stress-mediated beta-cell dysfunction and death

Autophagy:

Catabolic degradation of dysfunctional proteins and defective cellular components

Autophagy in Type II diabetes:

Initially protective against oxidative/ER stress, but persistent metabolic stress causes dysregulation and beta-cell dysfunction/death

Islet inflammation:

Macrophage infiltration with cytokine/chemokine release that contributes to beta-cell dysfunction/death

What transcription factor is involved in islet inflammation?

NF-κB

What cytokines can beta cells produce in Type II diabetes?

IL-1β, IFNγ, TNFα, and IL-6

What can proinflammatory signals activate in beta cells?

Apoptotic mechanisms, ER stress, and UPR

Islet amyloid:

Pathologic pancreatic lesion formed by abnormal aggregation of islet amyloid polypeptide

What percent of Type II diabetes patients have islet amyloid?

More than 90%

Islet amyloid polypeptide:

Beta-cell hormone coproduced and cosecreted with insulin

What does increased islet amyloid deposition correlate with?

Decreased beta-cell mass and insulin production

How do GLP-1 receptor agonists and DPP-4 inhibitors help beta cells?

Enhance beta-cell proliferation/function through EGFR-mediated PI3K/Akt and cAMP/PKA pathways