• synthesized in pancreatic β cells as proinsulin
• proinsulin is processed to form C-Peptide and  insulin
• all commercially available insulin contains only active insulin peptide
• controls storage and metabolism of carbohydrates, proteins, and fats (activity occurs 1º in liver, muscle, & fat tissue)

release from pancreas is stimulated by increased blood glucose, incretins, vagal nerve stimulation, ...etc.

(incretins = local hormones produced in GI tract)

1. Facilitates entry of glucose into muscle, adipose and several other tissues 
2. stimulates liver to store glucose as glycogen
   • both 1 & 2↓ [glucose] in blood
3. Stimulates lipogenesis (liver)
4. Inhibits lipolysis (release of FFA from adipose)
5. Stimulates protein synthesis
6. Promotes an intracellular shift of K+ and Mg+, thus appears to temp. ↓ elevated blood [ ] s of theses ions

• Impaired insulin secretion (Type I)
• Abnormal muscle and fat metabolism → insulin resistance (Type II)
• Increased hepatic lipid production

less glucose utilization at muscle, liver, fat →  

 ↑ hepatic glucose output → hyperglycemia

• Recombinant DNA tech now exclusively used
• consist of the aa sequence of human insulin or variations thereof
• animal source insulin no longer used

• Rapid acting (e.g. insulin analogs aspart, lispro)
• Short acting (e.g regular insulin)
• Intermediate acting (e.g. NPH)
• Long-acting (e.g. insulin analogs glarginie and detemir)

given around meals

(rapid and short acting insulin)

• differ mainly in onset, peak and duration of action following SC administration
• by adding either protamine or zinc to pure insulin, its action can be prolonged
• inter-individual and intra-individual variation in above values may occur based on site of injection, injection tech., tissue blood supply, temp., presence of insulin Abs., exercise, excipients in insulin formulations, and individual response

• given regardless of meals, at constant longer acting levels 
• no peak
• provide insulin required to maintain body functions
• long acting and intermediate (mostly considered basilar, but gives a peak: does not last all day)

• Insulin Analogs
• Better for paitents than regular insulin b/c:
  • Onset is quicker, peak is closer to hyperglycemic effect due to meals, and duration is shorter so hypoglycemic effect is not prolonged past meals
• Examples: Aspart, lispro, inhalation 

mostly considered basilar, but gives a peak and does not last all day (duration = 10-16 hrs)

• example: NPH

insulin analogs glargine, detemir

provide constant low levels of insulin for entire day

• usually contain intermediate with short acting insulins
• provide short onset with prolonged duration 
• must be given with meals (or will cause hypoglycemia)
• not good choice for newly diagnosed patients

• Rapid acting (prandial) insulin preparations
• equal or better efficacy than regular insulin
• less hypoglycemia than regular insulin

• Rapid acting insulin prep
• significant respiratory side effects (↓ FEV, infections, cough)

• inject SC 30-45 min before meal
• can be used IV: immediate action, shorter duration

• addition of protamine results in longer duration and more delayed peak compared with regular insulin
• given 1 or 2x per day
• considered basal insulin
• evening admin can cause nocturnal hypoglycemia

• peak-less basal insulin
• pH = 4: precipitates upon injection (in neutral body pH) and acts as depot providing slow continuous release

• exhibits intermediate and long acting action
• dose-dependent onset and duration of action
• considered a basal insulin

• hypoglycemia
• insulin allergy
• immune insulin resistance
• lipodystrophy at injection sites

Conscious patient:

Dextrose tablets (1st choice)

orange juice or glucose gel

Unconscious patient:

IV dextros 50% (if IV access available)

Glucagon IM

2 classes:

Sulfonylureas (2nd generation agents)

Meglitinides

- Both classes have same mech of action:

promote insulin secretion from β cells of pancreas

- Classes have different PKs

• a class of insulin secretagogues
• used as monotherapy or in combo 
• average ↓ in HgA_1C = 1.5%
• Main adverse effects:
  • weight gain
  • Hypoglycemia
• frequent loss of efficacy over long period of time (due to depletion of insulin from β cells) (add another agent if this occurs)

• due to gradual loss of β cell function, glucose lowering effect plateaus at ≈ 1/2 max recommended dose
• therefore, do not give patient more than 1/2 max recommended dose. Will achieve better results if a 2nd agent is added instead
• start slow an ↑ q2-4 weeks (especially in elderly with renal insufficiency)

Glyburide

Gliqizide

Glimepiride

t1/2: 5-10 hrs

duration: glyburide and glimepride 24 hrs; glipizide 12-24 hrs

Metabolism: Mainly Hepatic, also renal component

• class of insulin secretagogues
• oral agents that act like insulin
• controls post-prandial hyperglycemia
• ↓ dose in elderly or pts not previously treated with hypoglycemic agents
• Adverse effects: Weight gain, Hypoglycemis

• rapid and complete oral absorption
• Hepatic metabolism, with some renal excretion
• shorter duration, onset, and t1/2 than sulfonylureas

Metformin / glucophage

• average ↓ in HbA_1C = 1.5%
• used as monotherapy or in combination with other agents

• Main mechanism: ↓ hepatic glucose production by ↑ hepatic sensitivity to insulin
  • requires insulin therefore, only used for type II
• 2º mechanisms: ↑ peripheral glucose uptake & utilization
  • insulin sensitizer (counters insulin resis.)
• Other metabolic effects:
• ↓ triglycerides and LDL, ↑ HDL (?)
• weight reduction or stabilization
• impairs hepatic metabolism of lactic acid

• Onset: within days
• negligible protein binding
• Not metabolize by liver
• excreted in urine (90% unchanged)

• Renal disease
  • serum creatinine > 1.5 mg/dl in males, or 1.4 in females
• alcoholism
• hepatic disease
• conditions predisposing to tissue anoxia (due to risk of lactic acidosis)
• Hold for 48 hrs after radiologic tests using iodinated contrast (can be renally toxic)

• GI (20%) - titrate dose slowly, give with food, or use extended release form)
• <1% lactic acidosis (dose related)
• ↓ B₁₂ absorption (with long term therapy)

• obese patient with type II diabetes mellitus
• normal kidney function
• no contraindications or other conditions predisposing to development of lactic acidosis

• improve insulin sensitivity via multiple actions on gene regulation (requires insulin)
• Stimulate a nuclear receptor peroxisome proliferator-activated receptor (PPARγ) 1º in adipose, and less so in muscle and liver
• Promotes glucose uptake by adipose, spare skeletal muscle, and liver from harmful metabolic effects of high FFFA (keeps fat where it belongs) 

Piglotazone 

Rosiglitazone

combination products: Avandemet, avandaryl, ActoPlusMet

• onset of action takes weeks to months
• extensive liver metabolism by CYP450, excretion not renal dependent
• High protein binding >99%

• used as mono or combo therapy
• do not contribute to hypoglycemia
  • combo of TZD and metformin has advantage of not causing hypoglycemia
• Average ↓ HgA_1C = 1%
• long term: ↓ triglycerides, slight ↑ HDL and LDL (minor effects)

• Weight gain (dose related)
• Fluid retention
  • presents as anemia (↓ Hgb adn Hct) and peripheral edema
  • occurs more frequently when used in combo with insulin
  • may precipitate heart failure (not recommended for class III or IV HF)
• Hepatotoxicity: hepatic failure, hepatitis

• "Starch blockers"
• produces modest drop in HgA_1c 0.5-1%
• Not absorbed systemically, therefore lack hypoglycemia and weight gain
• hypoglycemia may occur with concurrent sulfonylurea treatment
• Rarely used as monotherapy due to mild efficacy

Acarbose

Miglitol

• work locally in GI
• competitively inhibit intestinal a-glucosidases at brush border and ↓ postprandial digestion and absorption of starch and disaccharides

• GI: flatulence, diarrhea, and discomfort (due to undigested carbs reaching lower bowel where gas is produced by bacterial flora)
  • products containing alpha glucosidase (i.e. beano) interfere with therapeutic action and are contraindicated in combo
  • use antacids and bismuth for relief of GI side effects

• patients with inflammatory bowel disease or any intestinal condition that could be worsened by gas and distention
• Miglitol should not be used in renal failure

Miglitol: urine (95% unchanged drug)

- do not use in renal failure

Acarbose: mostly fecal; urine (2%)

• insulin response to an oral glucose load exceeds that measured after IV administration of equivalent amount of glucose

• Hormones that produce gut-derived signals in response to oral nutrient intake 
• stimulate glucose dependent insulin secretion
• inhibit glucagon release
  • both these actions lower blood glucose 

• Gastric inhibitory polypeptide (GIP)
• Glucagon like peptide-1 (GLP-1)

• GIP: effects on insulin secretion are weak or absence in type 2
• GLP-1: insulin secretion in response to GLP-1 are mostly preserved
  • can use GLP-1 as mediator to insulin secretion

• short t1/2 of 2 minutes
• many options now available to ↑ t1/2:
  • Incretin mimetics
  • DPP-4 inhibition

Exenatide

Liraglutide

analogues of GLP-1, prolong t1/2 of GLP-1

• GLP-1 analogues (stimulate glucose dependent insulin secretion)
• ↓ HgA1c by additional 1%, when adjunct to sulfonylureas or metformin
• Weight loss has been demonstrated
• slows gastric emptying, ↓ post-prandial glucagon secretion (lowers hyperglycemia after meals)

• Exenatide: not recommended in ClCr < ml/min
• no dose adjustment of Liraglutide is reccommemded with kidney impairment
• administer other meds at least 1 hr prior to incretin mimetics to avoid ↓ rate of absorption (due to slowing of gastric emptying)

• nausea and vomiting (up to 44% with higher doses) generally subsides with continued use
• Hypoglycemia (only if given with sulfonylurea)

• Prevent breakdown of GLP-1 and enhance GLP-1 function
• referred to as "gliptins"

• GLP-1 is rapidly degraded by DPP-4 enzyme. 
• DPP-4 found throughout body, but highest [ ]s found in intestines, kidneys, lymphocytes, and bone marrow
• DPP-4 inhibitors prevent degradation of incretin hormones by DPP-4, thereby enhancing their fxn to ↑ insulin release and ↓ glucagon levels in circulation

Sitagliptin

Saxagliptin

• adjunct to diet and exercise to improve glycemic control in type 2 diabetes
• monotherapy or combo with metformin or TZD, when single agent with diet and exercised does not provide adequate glycemic control

• stimulation of insulin secretion
• inhibition of glucagon secretion
• do not slow gastric emptying or cause weight loss (in contrast to GLP-1 agonists)

• reduce dose of sitagliptin and saxagliptin in renal failure

• generally mild
• upper respiratory tract infection, headache, nasopharyngitis, pancreatitis (sitagliptin)
• do not cause severe hypoglycemia or weight gain

         GLP-1 analogues DPP-4 inhibitors

Incretin:   Mimetic ;enhancer

Nausea: More; Less

GI effects: significant; fewer

weight: loss; neutral

renal dys: not reccommended; adjust dose

HgA1c ↓: .8-1%; 0.6-0.8%

form: injectable; tablet

• Hormone, co-secreted with insulin by β cells
• Type 1 diabetes: absolute deficiency of amylin and insulin
• Type 2: relative deficiency of amylin and insulin
• amylin replacement may provide benefits when combined with insulin, and can be used with type 1 & 2 DM

• delays gastric emptying
• suppressed glucagon secretion
• ↓ appetite and produces weight loss (central mechanism)

• ↑ risk of insulin-induced hypoglycemia
  
  • most common in 1st 3 months of therapy
  • in both type 1 & 2 DM
  • occurs with in 3 hrs of injection
  • ↓ prandial insulin dose by 50% when pramlintide is started
• GI: Nausea, anorexia, vomiting
• slight weight loss

• give immediately before meal by injection
• ↓ prandial insulin dose by 50% when pramlintide is started

• only as adjunctive therapy with mealtime insulin in patients with type 1 or 2 diabetes who have failed to achieve desired glucose control despite optimal insulin therapy.
  • in type 2: may be used with or without sulfonylureas or metformin
• ↓ in HgA1c is minimal (0.3-0.4%)

Adrenocorticoids = steroid hormones secreted by the adrenal cortes. (aka adrenal steroids)

2 classes:

1. Glucocorticoids 
2. Mineralocorticoids

• class of steroid hormones, released by adrenal cortex
• affect carbohydrate metabolism
• eg. cortisol, hydorcortisone

• class of steroid hormones, released by adrenal cortex
• affect electrolyte and water balance in body tissues
• e.g. aldosterone

3 layers:

1. outer = zona glomerulosa: produces mineralocorticoids
2. Middle = zona fasciculata: produces glucocorticoids
3. inner = zona retucularis: produces adrenal androgens

• bind specific cytoplasmic receptor targets in tissue
• receptor-hormone complexes translocated into nucleus and attaches to gene promotor elements to turn genes on or off (depending on tissue)

Glucocorticoid receptors: widely distributed throughout the body

Mineralocorticoid receptors: confined to excretory organs (kidney, colon, salivary and sweat glands)

structure determines biological activity (glucocorticoid vs. mineralocorticoid)

• hydrocortisone has equal activity at both receptor types
• others have strong preference 

• ↑ gluconeogenesis, antagonize actions of insulin
• ↑ serum glucose (hyperglycemia)
• Glycogen synthesis
• inhibit peripheral glucose uptake

• Protein (negative nitrogen balance), except liver
• Stimulate lipolysis
• lymphoid tissue (produce lymphocytopenia)
• Muscly, C.T., bone, skin atrophy
• Peripheral fat (↑ fat redistribution from peripheral to central areas of body)

• ↓ Calcium and iron absorption
• ↑ acid, pepsin (can ↑ chance of ulcer)
• ↓ local immune response against H. pylori 
• antiemetic activity

• Euphoria and behavioral changes
• ↑ alpha rhythm of EEG and induce depression

• ↑ in neutrophil count and platelets (WBC will ↑ after few days of use)
• ↓ in lymphocytes (T and B cells), monocytes, eosinophils, and basophils
• inhibit function of tissue macrophages  and T cells (↓ phagocyte competence)

• ↑ reabsorption of water, sodium, chloride
• ↑ excretion of potassium, calcium

1. during long term use, HPA axis suppression develops (atrophy of adrenal cortex)
2. inhibit Vitamin D mediated absorption of Ca+
   • may lead to hyperparathyroidism, therefore to an increase in bone resorption
   • long term use may lead to osteoporosis

(Hypothalamic-pituitary-adrenal)

• this depends on dose, frequency, time of administration & duration of glucocorticoid use
• patients develop cushingoid (hypercorticism) features
• chronic use should be tapered slowly with gradually decreasing doses

• withdrawal following long term use (> 2 wks) with pharmacologic dosages of systemic glucocorticoids should be very gradual until recovery of HPA axis function occurs
• many methods for this described

•  
  • peptic ulcer
  • heart failure
  • certain infectious illnesses (varicella and TB - immune suppressed pts)
  • psychoses
  • diabetes 
  • osteoporosis

Mitotane

Aminogluethimide

Ketoconazole

Metyrapone