Diabetes Mellitus - Basics and Non-Insulin Therapy

Question 1

What are the benefits of having good glycemic control?

Answer 1

• significantly slows onset of complications of disease (retinopathy, neuropathy, nephropathy)
• “metabolic memory” - good control early will delay complications later

Question 2

Describe the pathogenesis of T1 and T2 DM

Answer 2

T1: autoimmune destruction of pancreatic beta cells - insulin therapy is required
T2: progressive insulin secretory defect and inppropriately high glucagon after meals

Question 3

What are the general treatment concepts that you want to address with a newly diagnosed diabetic patient?

Answer 3

• diet and weight optimization
• increasing physical activity
• self monitoring of blood glucose and ketones
• patient self-management education and training
• reduce CV risk (stop smoking, get BP and lipids down)

Question 4

Why is there a greater insulin response to oral glucose than there is to IV glucose?

Answer 4

• incretin Glucagon-like peptide 1 (GLP1) secreted by the L cells of the ileum and colon in response to incoming nutrients
• GLP1 stimulates insulin secretion, slows gastric emptying, suppressed glucagon secretion, promotes satiety
• GLP1 is metabolized by DPP4
• secretion of GLP1 is impaired in T2DM

Question 5

What might be some indications in your patient that would allow your glycemic target to be a little higher (HbA1C around 8%)?

Answer 5

• patient is older with long standing disease, has multiple comorbidities, or is especially prone to hypoglycemia
• if the patient is young, you want to shoot for much lower! (A1C ~ 6%)

Question 6

What is the current recommendation for therapy of T2DM at initial diagnosis?

Answer 6

• initiate metformin with lifestyle interventions
• if this doesn’t work in 3 months, add a second oral agent, a GLP1 receptor agonist, or insulin
• if at first onset they are markedly symptomatic or have very elevated A1C, consider insulin therapy right away

Question 7

How does metformin work? What are the important advantages to this medication when compared with other oral treatments?

Answer 7

• MOA: activates AMP-kinase to decrease hepatic glucose production (primarily overnight to lower fasting glucose), decrease intestinal glucose absorption, and increase insulin action
• Advantages: no weight gain and no hypoglycemia
• SE: GI symptoms and rare lactic acidosis
• metformin is the 1st DOC for treating T2DM

Question 8

Name the drugs that work by closing K(ATP) channels on beta cell plasma membranes

Answer 8

1) sulfonylureas (glibenclamide/glyburide, glipizide, gliclazide, glimepiride)
2) meglitinides (repaglinide, nateglinide) - these are more rapidly acting than the sulfonylureas, take with meal!

• both classes work to increase insulin secretion, but run the risk of hypoglycemia and cause weight gain

Question 9

How does pioglitazone work?

Answer 9

• this is a thiacolidinedione that works by activating the nuclear transcription factor PPAR to increase peripheral insulin sensitivity
• Good: no hypoglycemia, increase in HDL, decrease in TG
• Bad: weight gain (a lot), edema, bone fractures, increased risk of bladder cancer

Question 10

How does rosiglitazone work?

Answer 10

• this is a thiazolidinedione (just like pioglitazone, but with different pros and cons) that works by activating the nuclear transcription factor PPAR to increase peripheral insulin sensitivity
• Good: no hypoglycemia, no association with bladder cancer
• Bad: increase LDL, weight gain, edema, bone fractures, increased CV events

Question 11

Name two drugs that work by slowing the breakdown of ingested carbs. Which enzyme do they interfere with?

Answer 11

• acarbose and miglitol, which are both alpha-glucosidase inhibitors
• peak glucose levels are not as high due to a slower glucose absorption
• Good: weight neutral, no hypoglycemia, medication stays in gut
• Bad: GI symptoms, only very modest reduction in A1C

Question 12

Two classes of drugs work on the incretin system. What are these drugs, and describe their pros and cons

Answer 12

• remember, incretins work to increase insulin and decrease glucagon, as well as slow gastric emptying and increase satiety

1) GLP1 agonists (exenatide, liraglutide)
- Good: weight reduction, improved beta cell function
- Bad: GI symptoms, acute pancreatitis risk, hypoglycemia

2) DDP4 inhibitors (sitagliptin, vildagliptin, saxagliptin, linagliptin)
- Good: no hypoglycemia, weight neutral, relatively few adverse side effects!

Question 13

Let’s say I want to get really crazy and l reduce my patient’s glucose levels by increasing their urinary glucose excretion (what could go wrong?). What drug do I give them?

Answer 13

• canagliflozin, a SGLT2 inhibitor that decreases glucose reabsorption in the kidney
• Good: no hypoglycemia, possible weight loss
• Bad: volume depletion, renal impairment, hyperkalemia, UTI’s, increased LDL

Question 14

How does bromocriptine (a dopamine-2 agonist) help in T2DM?

Answer 14

• alters hypothalamic regulation of metabolism and increases insulin sensitivity
• good: no hypoglycemia
• bad: dizziness, nausea, fatigue, rhinitis

Question 15

Let’s recap. Which noninsulin therapies are good because there is no or very little risk for hypoglycemia?

Answer 15

• metformin
• thiazolidinediones (pioglitazone, rosiglitazone)
• alpha glucosidase inhibitors (acarbose, miglitol)
• DDP4 inhibitors (sitagliptin, vildagliptin, saxagliptin, linagliptin)
• SGLT2 inhibitor (canagliflozin)

Question 16

What puts a patient at increased risk for hypoglycemia? What are some symptoms to look out for? Recommendations for treatment?

Answer 16

• At risk: greater than 60 yo, impaired renal function, poor nutrition, liver disease, increased physical activity
• Symptoms: confusion, slurred speech, sweating, shaking, hunger, headache, mood/behavior change, tingling, vision change, unconsciousness, seizures
• Recommendations: get some sugar in them! Glucose or glucagon ASAP to save brain function. In the hospital, use IV dextrose

Question 17

When is amylin secreted and what does it do? What drug is an amylin analog?

Answer 17

• released with insulin from beta cells in response to eating
• works to slow gastric emptying, suppress postprandial glucagon secretion, and reduce appetite
• injecting the analog, pramlintide, before each meal is useful to reduce insulin requirements (however, there is a significant risk of hypoglycemia if not careful)