A. Physiology

1. Synthesized in ß cells of the pancreatic islets
2. Gene gives rise to single chain preproinsulin polypeptide
   1. Preproinsulin has 23-amino acid leader sequence cleaved to give proinsulin
   2. Proinsulin has disuflides crosslinked
   3. Endoproteases in secretory vessels cleave an internal sequence of crosslinked proinsulin
   4. Internal C-peptide is removed from proinsulin (1:1 molar ratio C-peptide to insulin)
3. Mature insulin consists of disulfide linked A and B polypeptides, both chains required
4. Regular insulin is slowly absorbed [25]
   1. Regular insulin exists primarily as dimers
   2. When these dimers complex with zinc forming hexamers
   3. These larger hexamers diffuse slowly into the circulation
5. Insulin Receptor
   1. Insulin binds mainly to insulin receptor (InsR)
   2. InsR consists of 4 chains disuflide linked, 2 alpha and 2 beta subunits
   3. The alpha chains are 135K, external and contain Insulin binding domains
   4. The ß-chains are 95K, transmembrane spanning, with ATP binding and kinase domains
   5. The ß-subunit kinase activity autophosphorylates and is specific for tyrosine
   6. Binding of insulin to InsR leads to InsR phosphorylation of InsR and other proteins
   7. These other proteins are called InsR substrates 1 through 4 (IRS-1 thorugh -4)
   8. IRS proteins interact with IRS docking adapter proteins after phosphorylation
   9. A variety of growth and regulatory proteins interact with Insulin through the IRS
   10. MAP kinase, PI-3 kinase, PK B, and other pathways are activated
   11. Some of these proteins interact with the glucose transporter (mainly Glut4)
   12. The main mechanism by which insulin increases glucose transport is by recruitment of intracellular glucose transport proteins to the plasma membrane
   13. Four glucose transport proteins are currently known

B. Glucose Transporters [3]

1. Essentially all organs use glucose
   1. Brain uses a great deal of glucose
   2. Kidney as well
2. Key Organs for glucose level regulation (insulin action sites)
   1. Liver
   2. Skeletal muscle
   3. Adipose Tissue
3. Types of Glucose Transporters
   1. Five known facilitated-diffusion glucose transporters, GLUT-1 through 5
   2. Sodium-linked glucose transporter in intestine and kidney
4. GLUT-1
   1. High concentrations in brain, red blood cells and endothelium
   2. Km glucose ~20mM
   3. Constitutive glucose transporter
5. GLUT-2
   1. High concentrations in kidney, small intestine, liver, pancreatic ß-cells
   2. Km glucose ~42mM
   3. Low affinity glucose transporter
   4. Main role appears to be sensing glucose concentrations in islets
6. GLUT-3
   1. High concentrations in neurons and placenta
   2. Km glucose ~10mM
   3. High affinity glucose transporter
7. GLUT-4
   1. High concentrations in skeletal and cardiac muscle cells and adipocytes
   2. Km glucose ~2-10mM
   3. Insulin responsive glucose transporter
   4. Translocates from intracellular vesicles to plasma membrane on insulin signalling
   5. Muscle is the principle site for insulin stimulated glucose transport
8. GLUT-5
   1. High concentrations in small intestine, sperm, kidney, brain, adipocytes, myocytes
   2. This is a fructose transporter
   3. Very low affinity for glucose

C. Types of Insulin [2,21,22,25]

1. Variety of Insulins Available [21,25]
   1. Lispro Insulin (Humalog®): onset 15 min; peak ~1hr; duration 5hr
   2. Aspart Insulin (Novolog®): onset 15 min; peak ~1hr; duration 5hr
   3. Glulisine Insulin (Apidra®): onset 15-20 min; peak ~1 hour; duration ~5 hr [30]
   4. Regular (Semilente): onset 0.5-1 hr; peak 3hr; duration ~6hr
   5. Intermediate acting (Lente, NPH): onset 2-4hr; peak 6-10 hr; duration 10-16 hr
   6. Long acting (Ultralente): onset 6-10hr; 10-16 hr peak; duration ~20 hr
   7. Insulin Glargine (Lantus®): onset 2-3 hr; no real peak; duration 20-24 hr []
   8. Insulin detemir [rDNA origin] (Levemir®): long-acting (up to 24-hour duration of action) recombinant human insulin analog
   9. Humulin® premixed recombinant human insulins (such as NPH+regular)
   10. Inhaled insulin (Exubera®) approved for patients with DM1 and DM2
   11. Combination of rapid onset with very long acting insulins likely optimal treatment
   12. Neutral protamine lispro (insulin lispro protamine) combination available
   13. Protamine crystalline aspart combination also available
   14. Oral insulins are being developed
2. Lispro Insulin (Humalog®) [7,8]
   1. Human insulin with lysine and proline residue substitutions
   2. Rapidly dissociates into monomers in subcutaneous (sc) tissue
   3. Has very rapid onset (15 minutes) and short duration of action
   4. Can be taken immediately before meals with excellent glucose control
   5. Can also be used sc every hour for uncomplicated diabetic ketoacidosis [24]
   6. Has 50% increased affinity for IGF-1 receptor, similar affinity for insulin receptor
   7. Shows better reduction in post-prandial glucose levels than regular insulin
   8. Reduced incidence of hypoglycemic events compared with regular insulin
   9. May be best used in conjunction with very long acting insulin (such as Ultra-Lente)
   10. Can be used safely in pregnancy [25]
   11. No clear defferences with any of the other rapid acting insulins [30]
3. Aspart Insulin (Novolog®) [10]
   1. Human insulin with aspartic acid for proline substitution position 28 on ß-chain
   2. Similar to lispro insulin, radid onset (within 15 minutes) and short duration of action
   3. Peak concentration 40-50 minutes; 3-5 hour duration
   4. May cause less late postprandial and nocturnal hypoglycemia than regular insulin
   5. Unclear if any major clinical benefits compared with lispro and regular insulin
4. NPH (Neutral Protamine Hagedorn) Insulin
   1. Single dose given in PM shown to be as effective as divided doses or single AM dose [11]
   2. Better control with less side effects than when given in AM
   3. This was true in Type II DM in many, but not all patients
5. Insulin Glargine (Lantus®) [2,4]
   1. Recombinant human insulin with modified A and B chains
   2. FDA approved for both Types I and II DM (as effective as older insulins)
   3. Given only once daily at bedtime - as effective as 2-3 doses of NPH insulin
   4. Duration 24-30 hours with extremely good control of glucose levels
   5. If not on long-acting insulin, then start with 10 units at bedtime
   6. Probably causes less hypoglycemia than other long-acting insulins
   7. Morning insulin glargine superior to bedtime insulin glargine or bedtime NPH insulin, all in combination with glimepiride, for glucose control and reduced hypoglycemia [23]
   8. Once-daily insulin glargine similar HbA1c control to thrice-daily prandial insulin lispro in DM2 patients on oral hypoglycemic agents and is more convenient [34]
6. Inhaled insulin (Exubera®) [26,31,32]
   1. Approved for preprandial administration for types 1 or 2 DM
   2. More rapidly absorbed (10-20 minutes) and eliminated than injected regular insulin
   3. More rapid glucose lowering effect than injected regular insulin
   4. Bioavailability ~10%
   5. Slightly less lowering HbA1c versus sc insulin, but much better patient acceptibility [32]
   6. Has been withdrawn from marketing due to poor uptake

D. Utility

1. Life sustaining of treatment for Type 1 DM
2. Also used in Type 2 DM in combination with other agents
3. Potent reductions in Hemoglobin A1c (HbA1c) levels in both types of DM
4. Reductions in disease complications in both Types 1 and 2 DM over long term
5. Reduces triglyceride levels and maintains HDL levels
6. In patients with newly diagnosed DM2, initial intensive insulin leads to improved ß-cell function and remission after 1 year compared with oral agents [13]
7. Hypoglycemia Risk
   1. Increases with improved glucose control [12]
   2. Type 1 DM patients with ACE DD genotype have >3X increased risk of hypoglycemia
8. Side Effects in Type 2 DM
   1. Weight gain
   2. Increased atherosclerosis
   3. Increased fibrinogen
   4. Adding metformin to insulin allows reduction of dose and weight gain [14]
9. Inhaled insulin is effective in Type 2 DM and does not cause weight gain [5]
10. Over time, intensive insulin therapy may have less impact on glycemic control compared with standard therapy, but still reduced progression of retinopathy and nephropathy [15]
11. Non-invasive glucose monitoring is close to approval (GlucoWatch) [16]

E. Dosing

1. Considerations
   1. Patient must learn blood sugar monitoring
   2. Consider using rapid onset insulin (Lispro, Humalog®) just prior to meals [7,17]
   3. Discuss symptoms of hypoglycemia with patient
   4. Tight glucose control with intensive insulin therapy is clearly beneficial in Type 1 DM [27]
   5. After 17 years' followup, intensive insulin reduced CVD ~50% and correlated with reduced HbA1c and albuminuria compared with standard insulin [28]
2. Initiating Insulin Therapy [9]
   1. In general, a combination of a prandial (mealtime) and a basal insulin should be used
   2. Prandial insulins include lispro, aspart, gluslisine, regular (likely inferior to others)
   3. Basal insulins including glargine, detemir, NPH (which all appear about equal)
   4. Type 1 DM - Usually 0.5-1U/kg for control, with frequent monitoring
   5. Type 1 DM empirically 2/3 of total dose in AM, 1/3 PM; 2/3 of each dose is NPH, 1/3 Reg
   6. Type 1 DM - splitting evening dose into short-acting insulin at dinner and NPH at bedtime reduces risks for nocturnal hypoglycemia and reduces HbA1c [18]
   7. Type 2 DM - usually begin 10-20U NPH qd, or 0.4-0.5U/kg NPH qd depending on history
   8. Insulin glargine provides control similar to NPH with less hypoglycemia
3. Insulin Pump [19]
   1. Delivers controlled basal rate of insulin subcutaneously
   2. Generally well tolerated but minor pain, some increased catheter site infection
   3. Patient can deliver additional doses with some models
   4. Overall, diabetic control is as good or slightly better than with frequent monitoring
   5. Cost to initiate therapy ~ $5000 US
4. Critical Illness [20,29]
   1. Hyperglycemia often present in acutely ill patients
   2. Counterregulatory hormones play major role: norepinephrine, glucocorticoids, others
   3. Various medications (above) and parenteral nutrition contribute
   4. Hyperglycemia is more detrimental to most acutely ill patients than hypoglycemia
   5. Therefore, hyperglycemia should be treated aggressively
   6. Close monitoring of plasma glucose is required, goal is average glucose 100mg/dL
   7. Insulin with glucose infusions are recommended to maintain 80-110mg/dL plasma glucose
   8. Clear morbidity (but not mortality) benefit of tight glucose control in medical ICU [29]

References

1. Gerich JE. 2002. Am J Med. 2002. 113(4):308
2. Owens DR, Zinman B, Bolli GB. 2001. Lancet. 358(9283):739
3. Shepherd PR and Kahn BB. 1999. NEJM. 341(4):249
4. Insulin Glargine. 2001. Med Let. 43(1110):65
5. Cefalu WT, Skyler JS, Kourides IA, et al. 2001. Ann Intern Med. 134(3):203
6. Skyler JS, Cefalu WT, Kourides IA, et al. 2001. Lancet. 357(9253):331
7. Pimenta W, Korytkowski M, Mitrakou A, et al. 1995. JAMA. 273(23):1855
8. DCCT Research Group. 1993. NEJM. 329(14):977
9. Mooradian AD, Bernbaum M, Albert SG. 2006. Ann Intern Med. 145(2):125
10. Insulin Aspart. 2001. Med Let. 43(1115):89
11. Bailey CJ and Turner RC. 1996. NEJM. 334(9):574
12. Ben-Ami H, Nagachandran P, Mendelson A, Edoute Y. 1999. Arch Intern Med. 159(3):281
13. Weng J, Li Y, Xu W, et al. 2008. Lancet. 371(9626):1753
14. Aviles-Santa L, Sinding J, Raskin P. 1999. Ann Intern Med. 131(3):182
15. DCCT Research Group. 2000. NEJM. 342(6):381
16. Tamada JA, Garg S, Jovanovic L, et al. 1999. JAMA. 282(19):1839
17. Gitlin N, Julie NL, Spurr CL, et al. 1998. Ann Intern Med. 129(1):36
18. Fanelli CG, Pampanelli S, Porcellati F, et al. 2002. Ann Intern Med. 136(7):504
19. Lenhard MJ and Reeves GD. 2001. Arch Intern Med. 161:2293
20. Montori VM, Bistrian BR, McMahon MM. 2002. JAMA. 288(17):2167
21. DeWitt DE and Hirsch IB. 2003. JAMA. 289(17):2254
22. DeWitt DE and Dugdale DC. 2003. JAMA. 289(17):2265
23. Fritsche A, Schweitzer A, Haring HU, et al. 2003. Ann Intern Med. 138(12):952
24. Umpierrez GE, Latif K, Stoever J, et al. 2004. Am J Med. 117(5):291
25. Hirsch IB. 2005. NEJM. 351(2):174
26. Rosenstock J, Zinman B, Murphy LJ, et al. 2005. Ann Intern Med. 143(8):549
27. DCCT Research Group. 1996. JAMA. 276(17):1409
28. DCCT Research Group. 2005. NEJM. 353(25):2643
29. Van den Berghe G, Wilmer A, Hermans G, et al. 2006. NEJM. 354(5):449
30. Insulin Glulisine. 2006. Med Let. 48(1233):33
31. Inhaled Insulin. 2006. Med Let. 48(1239):57
32. Ceglia L, Lau J, Pittas AG. 2006. Ann Intern Med. 145(9):665
33. McMahon GT and Arky RA. 2007. NEJM. 356(5):497
34. Bretzel RG, Nuber U, Landgraf W, et al. 2008. Lancet. 371(9618):1073