Treating Diabetes

Question 1

What pathogenic changes are associated with type 1, 2, 3, and 4 diabetes?

Answer 1

• type I: autoimmune destruction of beta-islet cells
• type II: desensitized beta-islet cells or insulin-resistant peripheral tissues
• type III: non-pancreatic causes
• type IV: gestational diabetes

Question 2

What are the treatment goals of diabetes?

Answer 2

treat the hyperglycemia to avoid long-term complications

• fasting glucose< 120
• 2-hour postprandial glucose < 150
• A1c < 7

Question 3

Generally speaking, what group of drugs are used to treat type 1 diabetics?

Answer 3

insulin alone

Question 4

Describe insulin levels in those with type 2 diabetes.

Answer 4

• initially insulin levels rise as the pancreas attempts to compensate for the insensitivity of peripheral tissues
• eventually, the pancreas “burns out” and patients become insulin deficienct

Question 5

Describe endogenous insulin production.

Answer 5

• preporinsulin is produced
• the signal sequence is cleaved, leaving proinsulin
• C peptide is cleaved form the protein, leaving an alpha and beta chain linked by disulfide bonds

Question 6

Describe the mechanism by which beta-islet cells sense glucose levels and respond by release insulin.

Answer 6

• glucose is taken up via GLUT2, a low affinity transporter
• glycolysis generates ATP
• ATP closes a potassium channel in the surface, depolarizing the cell
• the resulting calcium influx tiggers exocytosis of insulin

Question 7

What intracellular change in beta-islet cells drives insulin release?

Answer 7

a growing ATP/ADP ratio, which signals the availability of energy, which closes potassium channels and depolarizes beta cells

Question 8

How does insulin act on peripheral tissues?

Answer 8

• it stimulates a tyrosine kinase receptor

- the resulting cascade induces expression of GLUT4 on the cell surface

Question 9

What is the net effect of insulin?

Answer 9

stimulate uptake of blood glucose by cells for use and storage

Question 10

Insulin is used in the treatment of which kinds of diabetics?

Answer 10

• it is the only therapy for type 1
• it is used in type 2, especially in the later stages when they become insulin deficient
• also used post-pancreatectomy and in gestational diabetes

Question 11

How do we classify our insulin therapies?

Answer 11

based on their duration of action

Question 12

How are insulins administered at home? Why?

Answer 12

subcutaneous injection avoids a quick rise or fall in response to digestive nutrients

Question 13

Insulin regimens are tailored to what aspects of a patient?

Answer 13

• activity
• diet
• endogenous insulin levels and responsiveness

Question 14

What is the primary adverse effect of insulin? What are other common side effects?

Answer 14

• hypoglycemia is the primary concern

- allergy, lipoatrophy, weight gain, and insulin edema are all possible

Question 15

Create a drug list

Answer 15

week 2, friday at 11

Question 16

Which sorts of insulins are typically prescribed to diabetics and what are typical dosing programs?

Answer 16

• start with a basal, low level insulin

- add a short-acting insulin to be administered just before eating if basal insulin isn’t sufficient

Question 17

List the rapid-acting insulins.

Answer 17

• Lispro
• Aspart
• Glulisine

Question 18

List the short-acting insulins.

Answer 18

• Regular Novolin

- Regular Humulin

Question 19

List the intermediate-acting insulins.

Answer 19

• NPH Humulin

- NPH Novolin

Question 20

List the long-acting insulins.

Answer 20

• Detemir

- Glargine

Question 21

What are NPH insulins?

Answer 21

intermediate-acting insulins: those attached to NPH, a slowly dissolving crystal component

Question 22

Regular insulins act for what period of time?

Answer 22

peak between 2-4 hours after administration with continued effects for roughly 8-12 hours

Question 23

How long are deter and glargine active for?

Answer 23

nearly 24 hours

Question 24

How is diabetic ketoacidosis treated?

Answer 24

• IV infusion of regular insulin at a low rate
• possible addition of glucose to prevent hypoglycemia
• fluid and electrolyte replacement

Question 25

Why does diabetic ketoacidosis cause fluid and electrolyte imbalances?

Answer 25

- hyperglycemia exceeds the capacity for reabsorption of the PCT - excess glucose in the tubules pulls water out, leading to a diuresis - additionally, glucose and acidosis shift potassium out of cells and into the extracellular space - total potassium decreases as it is lost through the kidneys, despite a hyperkalemia

Question 26

Sulfonylureas

Answer 26

- a group of insulin secretagogues - they bind to and activate SUR1, a subunit of the K/ATP channel, which depolarizes the cell to promote insulin release - also function by decreasing hepatic clearance of insulin and inhibit glucagon release by stimulating somatostatin release - second generation drugs have higher affinity for SUR1 and greater activity but carry a greater risk for hypoglycemia as a result - used in type 2 diabetics - oral formulations, circulates bound to albumin, metabolized in the liver, and excreted in the urine - adverse effects include hypoglycemia, weight gain, and allergic reaction (sulfa drug) - contraindicated in type 1 diabetics, pregnancy, breast-feeding mothers, and those with hepatic or renal insufficiency as poor clearance increases risk for hypoglycemia

Question 27

Why might you use a first generation sulfonylurea rather than a second?

Answer 27

because the first generation have lower activity and therefore pose less risk for hypoglycemia

Question 28

Meglitinides

Answer 28

- a group of insulin secretagogues - similar to sulfonylureas except they aren't sulfa drugs (avoid allergy) and bind a different site to activate the K/ATP channel - nateglinide has a more rapid onset than repaglinide - major adverse effect is hypoglycemia - cleared by the liver and contraindicated in those with hepatic insufficiency

Question 29

How does nateglinide compare to repaglinide?

Answer 29

nateglinide has a more rapid onset than repaglinide

Question 30

Metformin

Answer 30

- a biguanide and first line therapy for type 2 DM - primary mechanism of action is by reducing hepatic gluconeogenesis, but it also increases insulin sensitivity - this is a euglycemic effect meaning that it helps maintain normal blood glucose levels without producing hypoglycemia - has the added effect of reducing plasma triglycerides - lactic acidosis is a rare, but life-threatening dose-related complication most often seen in those with renal insufficiency - GI side effects are common and may result in reduced B12 absorption - does not produce weight gain or hypoglycemia and is not a sulfa drug - taken with or after food and has a half life of 1.5-3 hours, not metabolized, excreted by the kidney

Question 31

Describe Metformin Lactic Acidosis

Answer 31

- a metformin toxicity - by blocking gluconeogenesis, it may impair hepatic metabolism of lactic acid - this is more common in those with renal insufficiency and is dose-related

Question 32

Thiazolidinediones (TZDs)

Answer 32

- a group of insulin sensitizers - they are PPARy agonists with some PPARa agonist activity (rosiglitazone has more PPARy affinity than pioglitazone) - in adipose tissue, PPARy promotes the transport of serum lipids to adipose tissue; in other tissues it promotes insulin sensitivity - as a result, there is less hepatic gluconeogensis and an enhanced uptake of glucose by skeletal muscles - they effectively reduce glucose and triglyceride levels - declining use because of significant weight gain, frequent hepatotoxicity, and congestive heart failure

Question 33

alpha-Glucosidase Inhibitors

Answer 33

- a group of drugs that inhibit intestinal glucose absorption - they inhibit pancreatic amylase and intestinal glucosidase enzymes, thereby increasing the time required to absorb complex carbs and reduce post-prandial glucose peaks - unpopular today because there effects have been exceeded by newer drugs, but occasionally used in combination with other drugs - pose no risk for hypoglycemia, but increased glucose is deliver to gut bacteria and so flatulence, bloating, and diarrhea are common - not recommended for those with IBD or individuals who spend lots of time in closed spaces

Question 34

Incretins

Answer 34

- GLP1/GIP analogs and inhibitors of dipeptidyl peptidase-4 (enzyme that degrades them) - they increase insulin release, decrease glucagon section, delay gastric emptying, and central suppression of appetite - effective in the treatment of diabetes and have the added benefit of weight loss - pose very little risk for hypoglycemia and GI upset is rare - no benefit from using a GLP analog with a DDP-4 inhibitor

Question 35

What is dipeptidyl peptidase-4?

Answer 35

an enzyme that degrades the incretins (GLP-1 and GIP) and are thus a target for diabetes therapy

Question 36

What are the physiologic roles of incretins?

Answer 36

- they increase insulin release and suppress glucagon release - they slow gastric emptying - they act on the hypothalamus to suppress appetite

Question 37

Where are the incretins produced? What mediates their release?

Answer 37

- they are produce by enteroendocrine L cells in the ileum | - they are released in response to nutrients entering the gut

Question 38

SGLT2 Inhibitors

Answer 38

- a group of drugs that inhibit reabsorption of glucose from the proximal renal tubules - effective at controlling type 2 DM and promotes weight loss - major side effects include genital/urinary tract infections due to glycosuria and osmotic diuresis leading to hypotension - not effective in those with chronic kidney disease

Question 39

What are considered first line mono therapies for the treatment of type 2 diabetes?

Answer 39

- metformin - incretins - SGLT-2 inhibitors

Question 40

Pramlintide

Answer 40

- an amylin analog - serves to blunt glucagon secretion, delay gastric emptying, and decrease appetite (much like the incretins) - preprandial use as an adjunct to inulin improves glucose control in type 1 and 2 DM - however, poses a risk for hypoglycemia and GI symptoms, so incretins are preferred - metabolized and excreted by the kidneys

Question 41

Covesevalam

Answer 41

- a bile acid sequestrate and cholesterol-lowering drug used for glucose control in type 2 DM - mechanism not fully known - can exacerbate hypertriglyceridemia - efficacy is modest and use questionable

Question 42

Bromocriptine

Answer 42

- a dopamine agonist that lowers glucose levels through an unknown mechanism - adverse effects include nausea, fatigue, dizziness, vomiting, and headache - efficacy is modest and use is questionable