Pharmacology of DM- 1 & 2 Flashcards Preview

MS2 Endocrine > Pharmacology of DM- 1 & 2 > Flashcards

Flashcards in Pharmacology of DM- 1 & 2 Deck (46):

What are the foundations of managing diabetes?


- Appropriate lifestyle modification

- Multifactorial risk reduction to prevent and treat macrovascular complications

  • HTN
  • Dyslipidemia
  • Body fat

- Prevent and treat microvascular complications

Glycemic control:

- For type 1: insulin ONLY; must always be "on board"

- For type 2: oral agents, insulin, combinations


What are the (3) main lifestyle modifications that should be made in managing diabetes?

- Diet

- Exercise

- Weight control


What are the general principals of a diabetic diet (Type I and II)?

Type I

- Under 60% carbs; keep carb proportions low (best for weight control)

- 30-35% fat: stick to healthy fats

- Limit salt and alcohol

Type II

- Same principles except may also want to limit total calories (reduction in energy intake to lower body weight in the obese)


What are the benefits of exercise on diabetes?

- Mechanism

- Guidelines

- Increases insulin sensitivity

- CV benefits

- 20 min/day, HR 120/min, DAILY (brisk walk)

- Acute effect and fades quickly, so need to do everyday


What are the benefits of weight loss on diabetes?

- Promotes insulin sensitivity (independent of exercise)

- Beneficial effect is proportional to central fat lost (deep visceral fat is what contributes to insulin sensitivity; liposuction of subcutaneous fat has no effect)

- Even loss of 3-5lb changes fasting glucose! (although may not have huge CV effect)

- CV benefits

- IBW: but ANY degree helps

- LookAHEAD: NIH trial that got 5% sustained body weight loss with CV effect being end result studied... not very encouraging results. No difference (can't compete with statin effect) BUT big change in glycemic control. Actually optimistic outcome (?)


What was found in DCCT/EDIC and follow up trials?

- HbA1C

- CV effects

- Glycemic control

- Microvascular effects

Dealing with Type I diabetics!

- HbA1C difference at close of study (better in intensive vs. conventional group)

- No change in CV effects at closeout (but only because it took longer for manifestations to come about)

  • Intensive insulin therapy reduced the risk of cardiovascular complications in type 1 diabetes

- No difference in glycemic control in trial follow up, BUT intensive therapy reduced the incidence of retinopathy and microabluminuria in type I diabetes


What was the population of the UKPDS study?

Type II diabetics


What was found in the UKPDS study?

- End point glycemic control

- Endpoints

- Follow up

Glycemic control

- Intensive therapy group had big drop in HbA1C down to normal level (under 6.5%); conventional group had tiny drop

- Initial HbA1C drop was not sustainable; both groups rose in parallel, but intensive group still lower. HbA1C remained below initial levels for 6 yrs


- Microvascular complications greatly reduced for intensive group (retinopathy, microalbuminemia reduced 20-30%)

- Macrovascular complications did not achieve statistical significance


- Glycemic levels converged

- Sustained benefits for intensive group, including CV effects (decrease in MI rates many years later)

Not quite as impressive improvements as type I study, but glycemic control is tremendously important, even if unsustained


Why, despite continuing therapy, was it that glycemic control/HbA1C was unsustainable in UKPDS study?

Thought to be due to progressive beta cell loss

- Inexorable increase in glycemia due to increasing lessening of insulin secretion


What are targets for glycemic control in Type II diabetes (organs and the problem)

- Drugs for each


- a-GSI

- Diet

- Incretins

Liver (increased glucose production)

- BG

- Insulin

Pancreas (impaired insulin secretion)

- SU

- Meglitinides

- Incretins

Kidneys (glycosuria)

- SGLT2 inhibitors

Muscle and Fat (receptor/post-recep defect and insulin resistance)


- BG

- Insulin

- Exercise


What are oral antihyperglycemic classes?

- Secretagogue

- Biguanide

- a-Glucosidase inhibitor

- Glitazone (TZD)

- Incretins

- SGLT2 inhibitors


What are secretagogue drugs?

- Sulfonylureas

- Repaglinide

- Nateglinide


What are biguanide drugs?

- Metformin


What are a-Glucosidase inhibitors?

- Acarbose

- Miglitol


What are Glitazone (TZD) drugs?

- Pioglitazone

- Rosiglitazone


What are incretins?

GLP-1 agonists:

- Exenatide

- Liraglutide

Dipeptidyl peptidase inhibitors:

- "Glipitins"


What are SGLT2 inhibitors?

- Dapagliflozin

- Canagliflozin


What is the mechanism of insulin secretagogues?

- Efficacy depends on what

- Power comparison

- Dosing

- Side effects

- Main risk

- Mechanism = basal and/or prostprandial insulin secretion

- Efficacy depends on functioning B cells

- Power of sulfonylureas > Nateg/Repag in terms of A1C decrease (0.5-1%)


- Sulfonylureas: 1-2x/day

- Repaglinide/nateglinide: 3-4x/day with meals

Side effects:

- Weight gain


Main risk = hypoglycemia


How do sulfonylureas work?

Normally, rise in glucose and transport into cell (GLUT2 transporter in Beta cell) causes rise in ATP

- Increased ATP:ADP ratio -> closure of K channel

- Cell depolarization -> opening of Ca channels

- Ca influx -> release of pre-formed insulin

Sulfonylurea drugs bind complex on K channel and close it themselves, resulting in insulin release

- Trouble is that they're not physiological (hold channel closed for long period of time)... If not eating appropriately, may become hypoglycemic


What is big difference between Sulfonylureas and Repaglinide/nateglinide?

Not as strong, but much shorter acting

- Can take right with meals to last duration of meal


What is the mechanism of Biguanides/Metformin?

- Efficacy depends on

- Power

- Dosing

- Side effects

- Main risk

- Mechanism: decreases hepatic glucose production

- Efficacy depends on presence of insulin

- Power: decreases A1C 1-1.5% (more than sulfonylureas)

- Dosing: 2-3x/day

Side effects:

- Diarrhea

- Nausea

Main risk = lactic acidosis


How does Metformin (MOA of French Lilac) work?

- Mechanism?

Metformin -> LKB-1 -> phosphorylation/activation of AMPK

- Decreased ACC activity (effects below)

- Decreased SREBP-1 expression/activity and thus less gene expression of FAS

  • Less hepatic FA, VLDL synthesis, increased FA oxidation
  • Less hepatic steatosis, increased liver insulin sensitivity

- Decreased hepatic glucose production

- Increased muscle glucose uptake

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What is the mechanism of a-Glucosidase inhibitors (Acarbose and Miglitol)?

- Efficacy depends on

- Power

- Dosing

- Side effects

- Mechanism: delay carbohydrate absorption

- Efficacy depends on postprandial hyperglycemia

- Power: decrease A1C 0.5-1%

- Dosing: 3x/day, with meals

- ASEs: Flatulence


Characteristics of Thiazolidinediones (Pioglitazone and Rosiglitazone)?

- Mechanism

- Efficacy depends on

- Power

- Dosing

- ASEs

- Main risk

- Mechanism: enhance tissue response to insulin by activating PPAR-g

- Efficacy depends on presence of insulin and resistance to its action

- Power: decrease A1C 0.9-1.6% (good!)

- Dosing: 1x/day


- Edema

- Weight gain

- Anemia

- Increased risk of MI (possible?); bad! opposite of desired effect

Main risk = congestive heart failure; [liver]


What effect does TZD have in human lipoatrophic diabetics?

- HbA1c improved 2.8%

- Fasting TG improved 230 mg/dL

- Fasting RQ decreased 0.12

- Total body fat increased 2.4% (subcutaneous, not visceral)

Having high body fat is bad in diabetes, but having no body fat is worse! Very hard to manage



How do GLP-1 and its agonists work in treating diabetes?

1. Mimic GLP-1 action

  • Exendin 4 (Exenatide)
  • Given with metformin or sulfonylurea, not insulin
  • Long acting in clinical trials

2. Prolonging GLP-1 effect

  • DDP-4 antagonists


How is beta cell function abnormal in type 2 diabetes?

A range of functional abnormalities is present

- Abnormal oscillatory insulin release

- Increased proinsulin levels

- Loss of 1st-phase insulin response

- Abnormal 2nd-phase insulin response

- Progressive loss of beta-cell functional mass


T/F: Insulin and glucagon dynamics in response to meals are abnormal in type 2 diabetics


- Delay/depressed insulin response to meals

- Nonsuppressed glucagon


What happens to the Incretin Effect in Type 2 diabetes?

Incretin Effect is impaired in Type 2 diabetes

- Shown by the difference between taking glucose orally vs. IV

  • If given IV, insulin rises but not terribly sharp (bypassing gut and incretin effect)
  • Oral administration results in sharp spike 

- Lose oral spike in type 2 diabetes (indicative of loss of incretin effect)

- In type 2 diabetes, you don't have proper insulin produciton, incretin effect or glucagon suppression


What are incretins? What effect do they have?

Intestinal hormones released in response to food ingestion

- Dominant incretins are GIP and GLP-1

  • GIP = glucose-dependent insulinotropic peptide
  • GLP-1 = glucagon like peptide I

- Greater stimulatory effect on insulin secretion with oral than with IV

- Stimulate insulin secretion in the presence of glucose

- Incretins account for up to 60% of the postprandial insulin response


What normally stimulates GLP-1 secretion?

- Effects in the human body


- Stimulated by food intake

- Diminished in IGT and diabetes

- Response to GLP-1 preserved even in diabetes


- CNS: promotes satiety and reduction of appetite

- Liver: decreases glucagon and thus hepatic glucose output

- Alpha cell: decreased glucagon secretion post-meal

- Beta cell: enhance glucose-dependent insulin secretion

- Stomach: regulates gasric emptying


How can the effects of GLP-1 and GIP be enhanced?

- DPP-4 inhibitor: prevents DPP-4 action and the inactivation of GPLP-1 and GIP


Which is more potent in peripheral glucose disposal, TZD or Metformin?

- Insulin sensitivity (endogenous glucose production)?

- TZD more potent in peripheral glucose disposal

- Metformin is vastly more potent in insulin sensitivity assessed by endogenous glucose production

These 2 are used in conjunction very well


Conclusions of Oral Treatment of Glycemia:

- Most oral agents control mainly fasting (basal) hyperglycemia

- Acarbose, miglitol, and nateglinide have the greatest effect on postprandial increments, but the least ability to reduce A1c

- Even with intensive treatment, monotherapy, with all agents tested thus far, tends to fail in the long term

- Combination therapy is required


What are contraindications for oral agents?

- Type 1 diabetes: recall, only use insulin!

- Pregnancy + lactation (relative C/I)

  • Sulfonylureas and perhaps Metformin are safe in pregnancy (although may not be most flexible/efficacious)
  • Insulin still best treatment for gestational diabetes (?)

- Concurrent acute or chronic illness (severe infection, hepatic or renal disease)

- Drug allergies


Describe the structure of insulin

- Produced by cleavage of pro-insulin into 2 chain molecule held together by disulfide bridges

- Manufactured as monomer and naturally forms dimers (self-aggregation in solution)

- When secreted, native insulin is a hexamer with a central core of zinc

- Only monomers are absorbed into bloodstream (why insulin action is somewhat delayed and variable person-person)


Describe insulin and its modified forms that are:

- Short acting

- Intermediate acting

- Long acting

Short acting: insulin

- Hexamers in Zn buffer

Intermediate acting: Neutral Protamine Hagedorn (NPH) Insulin

- Medium-sized crystals in Zn-protamine buffer

Long acting: Lente and Ultralente insulin

- Intermediate and large crystals in acetate-Zn buffer


What are the different insulin analogs?

- Structure

- Self-aggregation

Human insulin

- Hexamers in solution


- Limited self aggregation

- Monomers in solution


- Limited self aggregation

- Monomers in solution


- Soluble at low pH

- Preciptates at neutral (subcutaneous) pH


Describe the action profiles of insulin/analogs

- Regular


- Ultralente

- Aspart

- Lispro

- Glargine

- Aspart and Lipro have fastest increase and most peaked insulin serum levels (4-6 hr peak)

- Regular (6-8 hr peak)

- NPH (12-20 hr peak)

- Ultralente (18-24 peak)

- Glargine (24 hr peak)

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What treatment/combo are best for mimicing physiologic insulin release?

- Glargine to maintain fasting levels of insulin

- Lispro or Aspart 3x/day with meals


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What are the usual sites of insulin administration? Results?

- Upper arms

- Thighs

- Lower abdomen

- Buttocks

May result in insulin-induced lipoatrophy nad lipohypertrophy

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What is Amylin/Pramlintide?

- Mechanism

- Effects

- Given with what

- Co-localized with insulin in granules

- Co-secreted with insulin in normals


- Decreased post-meal glucose

- Suppress glucagon

  • Less liver glucose

- Slows gastric emptying

  • Satiety
  • Weight loss
  • Nausea

Given with Insulin



- Past diabetes therapies

  • Insulin resistance
  • More convenient insulin time of action

- Newer diabetes therapies

  • Beta cell dysfunction
  • Preservation or even increases in beta cells

Multifactorial Treatment

Diabetes Prevention



What are recommendations for A1C goal in (non-pregnant) adults in general?

- When should you be more stringent/go for lower A1C?

- When should you be less stringent?

- The A1c goal for non-pregnant adults in general is < 7.0%

- For selected individual patients, lower A1c goals may be recommended if the goal can be achieved without significant hypoglycemia or other adverse events, eg, patients with

  • Short duration of diabetes
  • Long life expectancy
  • No significant cardiovascular disease

- For some patients, less stringent A1c goals may be appropriate, esp if:

  • History of severe hypoglycemia
  • Limited life expectancy
  • Advanced microvascular or macrovascular complications
  • Extensive co-morbid conditions
  • Long-standing diabetes


How did endpoints (vascular morbidity) vary between conventional therapy and intensive therapy for multifactorial risk factors?

50% risk reduction in CV morbidity/mortality with intensive therapy


Therapies to aim for in the future?

- Preserve Beta cells

- Other therapies:

  • Biosensor pumps
    • "Bionic pancreas" that has improved glycemic control, fewer glycemic excursions, and less hypoglycemia
  • Islet cell transplantation
  • Islet regeneration