This document summarizes different types of anti-diabetic agents used to treat diabetes mellitus. It describes insulin and how it is synthesized, stored and secreted in the body. It also discusses oral anti-diabetic agents including insulin secretagogues, biguanides, thiazolidinediones, and alpha-glucosidase inhibitors; and how each group works to lower blood glucose levels. Complications from insulin therapy and factors affecting insulin absorption are also summarized.

1. Anti-diabetic Agents Florencia D. Munsayac, MD, FPSECP, MBA, RMT

3. The Endocrine Pancreas 1 million islets of Langerhans The islets are endocrine tissue containing four types of cells. In order of abundance, they are: beta cells , which secrete insulin and amylin; alpha cells , which secrete glucagon; delta cells , which secrete somatostatin gamma cells , which secrete a polypeptide.

4. Diabetes Mellitus Type 1 Diabetes - cells that produce insulin are destroyed - results in insulin dependence - commonly detected before 30 Type 2 Diabetes - blood glucose levels rise due to 1) Lack of insulin production 2) Insufficient insulin action (resistant cells) - commonly detected after 40 - eventually leads to β-cell failure (resulting in insulin dependence) Type 3 Diabetes Refers to multiple other specific causes of an elevated blood glucose Type 4 Diabetes (Gestational Diabetes) 3-5% of pregnant women in the US develop gestational diabetes

5. Diabetes Mellitus Incidence: 171 M worldwide (WHO 2006) Greatest prevalence: Asia & Africa Top 5 of the most significant diseases in developed world ADA: 18.3% (8.6M) of Americans age 60 

6. Diabetes – Insulin (synthesis, storage, secretion) This light micrograph of a section of the human pancreas shows one of the islets of Langerhans, center, a group of modified glandular cells. These cells secrete insulin, a hormone that helps the body metabolize sugars, fats, and starches. The blue and white lines in the islets of Langerhans are blood vessels that carry the insulin to the rest of the body.

7. Diabetes – Insulin (synthesis, storage, secretion) Insulin is a small protein consisting of an A chain of 21 amino acids linked by two disulfide (S—S) bridges to a B chain of 30 amino acids. Beta cells have channels in their plasma membrane that serve as glucose detectors. Beta cells secrete insulin in response to a rising level of circulating glucose .

8. Diabetes – Insulin (synthesis, storage, secretion) Chemistry: a small protein with molecular weight of 5808 contains 51 amino acids arranged in 2 chains ( A & B ) linked by disulfide bonds/bridges stored crystals consisting of 2 atoms of zinc & 6 molecules of insulin contain 8mg of insulin/human pancreas (=200 units)

9. Diabetes – Insulin (synthesis, storage, secretion)

10. Diabetes – Insulin (synthesis, storage, secretion) Regulation of Insulin Release Stimulants of insulin release Glucose, mannose Leucine Vagal stimulation sulfonylureas Amplifiers of glucose-induced insulin release Enteric hormones Glucagon-like peptide Gastrin inhibitory peptide Cholecystokinin Secretin, gastrin Neural amplifiers Beta receptor stimulation Amino acids arginine Inhibitors of insulin release Neural: alpha sympathetic effect of cathecolamines Humoral: somatostatin, amylin Drugs: diazoxide, phenytoin, vinblastine, colchicine

11. Diabetes – Insulin Insulin Degradation: - 2 main organs: liver – 60% kidney – 35-40% - hydrolysis of the disulfide bonds  glutathione insulin transhydrogenase (insulinase ) - half-life: 3-5 minutes Measurement of Circulating Insulin: - radioimmunoassay permits detection of insulin in picomolar quantities - basal insulin values: 5-15uU/ml (30-90pmol/L) - peak rise: 60-90uU/ml (360-540pmol/L)

12. Diabetes – Insulin (Biochemical Role) Tyrosine kinase receptors are the locks in which the insulin key fits Involved in signal transduction (insulin hormone being 1st messenger)

13. Effects of Insulin on its Targets Insulin affects many organs : It s timulat es skeletal muscle fibers . It s timulat es liver cells . It act s on fat cells It i nhibit s production of certain enzyme . In each case, insulin triggers these effects by binding to the insulin receptor . protein synthesis amino acids u ptake glucose uptake glycogen synthesis enzyme production glycogen breaking fat synthesis

14. Effects of Insulin on its Targets Transporters Tissues GlucoseKm (Mmo/L) Function GLUT 1 All tissues, esp.red cells, brain 1-2 Basal uptake of glucose; Transport across the BBB GLUT 2 B cells of pancreas; Liver; kidney; gut 15-20 Regulation of insulin release, other aspects of glucose homeostasis GLUT 3 Brain, kidney, placenta, other tissues < 1 Uptake into neurons, other tissues GLUT 4 Muscle, adipose 5 Insulin-mediated uptake of glucose GLUT 5 Gut, kidney 1-2 Absorption of fructose

15. Diabetes - Insulin Receptor The insulin receptor (IR) is a t ransmembrane g lycoprotein , composed of 2 α and 2 β domains. Its intracellular tyrosine kinase domain is activated by binding of insulin, leading to a cascade of signaling events.

16. Principal Types and Duration of Action 1. Rapid-acting insulins: Dispensed as clear solutions at neutral pH Contain small amount of zinc to improve stability & shelf-life Preferred for use in continuous SC infusion devices Insulin lispro, Insulin aspart, insulin glulysine, - Available in powder form for alveolar absorption human insulin recombinant inhaled

17. Principal Types and Duration of Action Pharmacokinetics: 6-7 hrs 2 hrs 10-20 min HIRI 3-5 hrs 1hr 5-15 min Insulin glulysine 3-5 hrs 1 hr 5-15 min Insulin aspart 3-5 hrs 1 hr 5-15 min Insulin lispro Duration Peak Onset Rapid-acting insulin

18. Principal Types and Duration of Action 2. Short-acting insulin Regular insulin A soluble crystalline zinc Made by recombinant DNA techniques Onset: 30 minutes Peak: 2-3 hours Duration: 5-8 hours Administered intravenously Useful in diabetic ketoacidosis, surgery or during acute infection, and when the insulin requirement is changing rapidly

19. Principal Types and Duration of Action 3. Intermediate-acting & Long-acting insulins a. LENTE INSULIN (insulin zinc suspension) mixture of 30% semilente with 70% ultralente insulin  provide a combination of relatively rapid absorption with sustained long action b. NEUTRAL PROTAMINE HAGEDORN or Isophane Insulin absorption & onset of action is delayed by combining appropriate amounts of insulin & protamine 6 molecules of insulin per molecule of protamine

20. Principal Types and Duration of Action c. INSULIN GLARGINE soluble, “peakless, ultra-long-acting insulin analog designed to provide reproducible, convenient, background insulin replacement Onset: 1-1.5 hours maximum effect: 4-5 hours Duration: 11-24 hours or longer given once a day

21. Principal Types and Duration of Action d. INSULIN DETEMIR Injected SC Binds to albumin via its fatty acid chain Administered b.i.d. Onset: 1-2 hours Duration: > 24 hours

23. Species of Insulin Beef and pork insulin The beef insulin differs by 3 amino acids, pork differs by 1 amino acid The beef hormone is most antigenic Human insulin Less expensive, less immunogenic Production by recombinant DNA techniques

24. Purity of Insulin chromatography Concentrations: 100 units 500 units

25. Insulin Delivery Systems A. Portable Pen Injectors - to facilitate multiple SQ injections B. Continuous Subcutaneous Insulin Infusion Devices (CSII, Insulin Pumps) - encouraged for individuals who are unable to obtain target control while on multiple injection regimens & where excellent glycemic control is desired, such as during pregnancy - velosulin (reg. insulin) & insulin aspart and lispro C. Inhaled Insulin - have a rapid route and a relatively short duration of action - used to cover mealtime insulin requirements - to correct high glucose levels

26. Factors that Affect Insulin Absorption: - site of injection: abdomen, buttock, anterior thigh, or dorsal arm - type of insulin - subcutaneous blood flow: massage, hot baths, or exercise - smoking - regional muscular activity at the site of the injection - volume & concentration of injected insulin - depth of injection

27. Complications of Insulin Therapy A. Hypoglycemia Mechanisms and diagnosis result from a delay in taking a meal unusual physical exertion dosage error CM: tachycardia, palpitations, sweating, tremulousness, hunger, nausea, convulsion, coma Treatment: glucose administration Glucagons 1 mg SQ or IM Honey or syrup

28. Complications of Insulin Therapy B. Immunopathology of Insulin Therapy 1. Insulin allergy an immediate type of hypersensitivity (IgE-antibodies) Tx: antihistamines, corticosteroids & desensitization 2. Immune insulin resistance (IgG antibodies) + circulating antibodies that neutralize the action of insulin to a small extent Tx: switching to a lesser antigenic purified insulin C. Lipodystrophy at injection sites corrected by avoidance of that specific injection site or with liposuction – hypertrophy

29. Oral Anti-diabetic Agents 4 Categories: a. Insulin secretagogues (sulfonylureas, meglitinides, D-phenylalanine derivatives) Biguanides c. Thiazolidinediones d. Alpha-glucosidase inhibitors

30. Insulin Secretagogues: A. Sulfonylureas Mechanism of Action: to increase insulin release from pancreatic B cells Sulfonylureas bind to S receptor  inhibits efflux of K+  depolarization  opens a voltage-gated Ca++ channel  results in Ca++ influx and the release of preformed insulin reduction of serum glucagon concentrations Chronic administration of sulfonylureas to type 2 diabetics reduces serum glucagon levels potentiation of insulin action on target tissues

31. Insulin Secretagogues: Sulfonylureas: 1 st generation tolbutamide tolazamide chlorpropamide acetohexamide 2nd generation glipizide glyburide 3rd generation glimepiride

32. Insulin Secretagogues: Tolbutamide: well absorbed but rapidly metabolized in the liver duration of action: 6-12 hours elimination half-life: 4-5 hours toxic reactions: skin rash hypoglycemia drug interactions: dicumarol, phenylbutazone, sulfonamides

33. Insulin Secretagogues: Chlorpropamide: duration of action: up to 60 hours half-life: 32 hours slowly metabolized in the liver 20-30% is excreted unchanged in the urine SE: hypoglycemia, hyperemic flush, dilutional hyponatremia, transient leukopenia, thrombocytopenia, jaundice CI: hepatic & renal insufficiency Dosage: 250mg daily

34. Insulin Secretagogues: Tolazamide: duration of action: 10-14 hours more slowly absorbed half-life: 7 hours SE: hypoglycemia

35. Insulin Secretagogues: Glyburide: metabolized in the liver short plasma half-life duration of action: 10-24 hours SE: flushing, hypoglycemia Contraindication: hepatic & renal insufficiency Dosage: 5-10mg as single morning dose

36. Insulin Secretagogues: Glipizide: has the shortest half-life: 2-4 hours duration of action: 10-24 hours 90% is metabolized in the liver 10% excreted unchanged in the urine SE: hypoglycemia Contraindication: renal & hepatic insufficiency Dosage: 5-20mg as a single dose, 30 minutes before breakfast

37. Insulin Secretagogues: Glimepiride: duration of action: 12-24 hours half-life: 5 hours available as once-daily dosing completely metabolized by the liver dosage: 1 mg daily

38. Insulin Secretagogues: B. Meglitinides Repaglinide: modulate B cell insulin release by regulating K+ efflux through the K+ channels no direct effect on insulin exocytosis peak concentration & peak effect: within 1 hour fast onset & duration of action (5-8 hrs.)

39. Insulin Secretagogues: B. Meglitinides Repaglinide: hepatically cleared by CYP3A4 half-life: 1 hour indication: controlling postprandial glucose excursions Dosage: 0.25-4 mg SE: hypoglycemia Caution: hepatic & renal impairment

40. Insulin Secretagogues: C. D-phenylalanine derivative Nateglinide: stimulates very rapid and transient release of insulin from B cells through the closure of ATP-sensitive K+ channel may suppress glucagon release early in the meal and result in less endogenous or hepatic glucose production has minimal effect on overnight or fasting blood glucose levels ingested just prior to meals

41. Insulin Secretagogues: C. D-phenylalanine derivative Nateglinide: absorbed within 20 minutes after oral administration time to peak concentration: < 1 hour hepatically metabolized by CYP2C9 & CYP3A4 half-life: 1.5 hours duration of action: < 4 hours SE: hypoglycemia but lowest of all the secretagogues

42. Biguanides Mechanisms of action: direct stimulation of glycolysis in tissues, with increased glucose removal from blood reduced hepatic & renal gluconeogenesis slowing of glucose absorption from the GIT, with increased glucose to lactate conversion by enterocytes reduction of plasma glucagon levels

43. Biguanides Metabolism & Excretion: Metformin: half-life: 1.5-3 hours duration of action: 10-12 hours not bound to plasma proteins not metabolized excreted by the kidneys as active compound may impair the hepatic metabolism of lactic acid

44. Biguanides Clinical Uses: refractory obesity whose BS is due to ineffective insulin action (insulin resistance syndrome) - only anti-diabetic drug that has been proven to reduce the complications of diabetes, as evidenced in a large study of overweight patients with diabetes (UKPDS 1998). use as in combination with sulfonylureas or thiazolidinediones in type 2 diabetics in whom oral monotherapy is inadequate dosage: 500mg TID

45. Biguanides Toxic Effects: anorexia, nausea, vomiting, abdominal discomfort, diarrhea absorption of B12 appears to be reduced during long-term therapy

46. Biguanides Contraindications: renal disease, alcoholism hepatic disease chronic cardiopulmonary dysfunction

47. Thiazolidinediones Increase the sensitivity of muscle, fat & liver to endogenous & exogenous insulin (“insulin sensitizers”) B inds to and activates the gamma isoform of the peroxisome proliferator-activated receptor (PPARγ) - PPARγ is a member of the steroid hormone nuclear receptor superfamily, and is found in adipose tissue, cardiac and skeletal muscle, liver and placenta Major site of action: adipose tissue -> promotes glucose uptake and utilization and modulate synthesis of lipid hormones or cytokines and other proteins involved in energy regulation Considered “euglycemics” Have a slow onset and offset of activity

48. Thiazolidinediones Side Effects: Hypoglycemia in combination Drop in triglyceride levels Slight rise in HDL & LDL cholesterol values Edema – fluid retention Anemia Dose-related weight gain (1-3 kg)

49. Thiazolidinediones CI: pregnancy Significant liver disease Heart failure

50. Thiazolidinediones Pioglitazone: may have PPAR-alpha as well as PPAR-gamma activity absorbed within 2 hours of ingestion metabolized by CYP2C8 and CYP3A4 to active metabolites DI: estrogen-containing oral contraceptives Taken once daily Dosage: 15-30mg Approved as monotherapy or in combination with metformin, sulfonylureas, and insulin

51. Thiazolidinediones Rosiglitazone: rapidly absorbed and highly protein bound metabolized in the liver by CYP2C8 & CYP2C9 administered once or twice daily dosage: 4-8 mg approved as monotherapy or in combination with biguanides & sulfonylureas

52. Alpha-Glucosidase Inhibitors are competitive inhibitors of the intestinal alpha-glucosidases and reduce the postprandial digestion and absorption of starch and disaccharides--> lowering post-meal glycemic excursions (45-60mg/dl) and creating an insulin-sparing effect members: acarbose miglitol

53. Alpha-Glucosidase Inhibitors taken in doses of 25-100 mg just prior to ingesting the first portion of each meal both are absorbed from the gut SE: flatulence, Diarrhea, Abdominal pain CI: Chronic or inflammatory bowel disease, Renal impairment, Hepatic disease (acarbose)

54. Pathophysiology of Type 2 Diabetes Insulin resistance. Beta cell dysfunction.

55. Pathophysiology of Type 2 Diabetes Insulin Resistance Insulin Resistance starts very early in the course of the disease. insulin resistance alone will not produce diabetes. If beta-cell function is normal, one can compensate for insulin resistance by increasing insulin secretion.

56. Pathophysiology of Type 2 Diabetes Beta cell defect all type 2 patients have at least a relative defect in both beta-cell function and mass. Function: in the (UKPDS), newly diagnosed people with diabetes had, on average, only about 50% of normal beta-cell function . [Diabetes. 1995;44:1249-1258 , Diab Res Clin Pract. 1998;40(suppl):S21-S25.] Mass: Autopsy studies comparing the volume of beta cells in non-diabetic individuals with that of people with diabetes found a 41% decrease in beta-cell mass among people with type 2 diabetes

57. Pathophysiology of Type 2 Diabetes Other Factors Two other factors: - Glucagon. - Gastric emptying.

58. Pathophysiology of Type 2 Diabetes The Glucagon Factor In response to a carbohydrate-containing meal, individuals without diabetes not only increase insulin secretion but also simultaneously decrease pancreatic alpha-cell glucagon secretion. The decrease in glucagon is associated with a decrease in hepatic glucose production, and along with the insulin response, results in a very modest increase in postprandial glucose. N Engl J Med. 1971;285:443-449.

59. Pathophysiology of Type 2 Diabetes The Glucagon Factor In contrast, the glucagon secretion in type 2 diabetics is not decreased, and may even be paradoxically increased. These insulin and glucagon abnormalities produce an excessive postprandial glucose excursion. more than 35 years ago, Roger Unger presciently stated, &quot;One wonders if the development of a pharmacologic means of suppressing glucagon to appropriate levels would increase the effectiveness of available treatments for diabetes”. N Engl J Med. 1971;285:443-449.

60. Pathophysiology of Type 2 Diabetes The Gastric Emptying Factor Many factors can affect the rate of gastric emptying. studies suggest that all other factors being equal, most people with type 1 and type 2 diabetes have accelerated gastric emptying compared to those without diabetes. Gastroenterology. 1990;98:A378.

61. Pathophysiology of Type 2 Diabetes One last observation In 1930 La Barre described a greater effect of oral rather parenteral glucose in increasing insulin secretion. In 1986 Nauck demonstrated that a glucose infusion graded to achieve plasma glucose levels identical of those achieved with oral glucose led to an insulin response that was only one quarter as great. J Clin Endocrinol Metab. 1986;63:492-498. Incretin hormones were discovered during researchers trials to find out interpretation to this phenomenon which has been called the incretin effect.

62. What are incretins? Hormones produced by the gastrointestinal tract in response to incoming nutrients, and have important actions that contribute to glucose homeostasis. Two hormones: - Gastric inhibitory polypeptide (GIP) . - Glucagon-like peptide-1 (GLP-1).

63. What are incretins? Gastric Inhibitory Polypeptide (GIP) Secreted by the K cells of the proximal gut. However, type 2 diabetes patients are resistant to its action (high blood level), making it a less attractive therapeutic target.

64. What are incretins? Glucagon-like peptide-1 (GLP-1) a 30-amino acid peptide secreted in response to the oral ingestion of nutrients by L cells, primarily in the ileum and colon. There are GLP-1 receptors in islet cells and in the central nervous system, among other places. GLP-1 is metabolized by the enzyme dipeptidyl peptidase-IV (DPP-IV) .

65. Actions of GLP-1 It enhances glucose-dependent insulin secretion. Inhibits glucagon secretion and therefore hepatic glucose production. Slows gastric emptying. Increases satiety resulting in less food intake. Appears to stimulate insulin gene transcription and insulin synthesis.

66. Actions of GLP-1 In animal studies it increases beta-cell mass by: - Decreasing beta cell apoptosis. - Stimulating the growth of new beta cells. Diabetes Care. 2003;26:2929-2940. ???... Long term benefit in reversing the progressive insulin deficiency.

67. Actions of GLP-1 Important , as glucose levels approach the normal range, the GLP-1 effects on insulin stimulation and glucagon inhibition declined (glucose dependence - reduction of hypoglycemia . - therapeutic advantage) Diabetologia. 1993;36:741-744

68. Actions of GLP-1 The Problem Unfortunately, GLP-1 is rapidly broken down by the DPP-IV enzyme (very short half-life in plasma - requires continuous IV infusion).

69. The Solution Two options: Incretin mimetics are glucagon-like peptide-1 (GLP-1) agonists. Dipeptidyl peptidase-IV (DPP-IV) antagonists - inhibit the breakdown of GLP-1.

70. Incretin mimetics Exenatide The first incretin-related therapy available for patients with type 2 diabetes. Naturally occurring peptide from the saliva of the Gila Monster. Has an approximate 50% amino acid homology with GLP-1. Binds to GLP-1 receptors and behaves as GLP-1.

72. Incretin mimetics Exenatide Resistant to DPP-IV inactivation. Following injection, it is measurably present in plasma for up to 10 hours. Suitable for twice a day administration by subcutaneous injection. Regul Pept. 2004;117:77-88. Am J Health Syst Pharm. 2005;62:173-181.

74. Weight Loss With Exenatide After adding exenatide: the group that was on metformin alone lost about 3 kg of body weight at 30 weeks, while the sulfonylurea group experienced a 1.5- to 2-kg weight reduction. Patients receiving metformin and a sulfonylurea in combination along with exenatide lost an average of 2 kg. Weight loss of up to 10 kg has been documented, but it varies from person to person. recently published findings have shown progressive weight loss continuing for 82 weeks. Patients convenience Diabetes Care. 2004;27:2628-2635, 2005;28:1092-1100, 2005;28:1083-1091. Diabetes, Obesity and Metabolism. 2006; 8(4):436; ISSN: 4.

75. Nausea With Exenatide was seen uniformly across the clinical trials, although most episodes were mild-to-moderate in intensity and generally intermittent. more frequent at the initiation of treatment and decreased over the course of several weeks.

76. Incretin mimetics Recent Advances Liraglutide: Another GLP-1 analog with longer half-life, similar to exenatide with once-daily injection . Diabetes Care. 2007;30:1608-1610 Long acting exenatide: Highly effective with once weekly injection . Diabetes Care. 2007;30:1487-1493

77. Dipeptidyl Peptidase-IV Antagonists The concept is to allow the endogenous GLP-1 to remain in circulation for a longer period. DPP-IV inhibitors are oral, rather than injectable. Weight neutral. associated with a low incidence of hypoglycemia or gastrointestinal side effects. Diabetes Care. 2004;27:2874-2880. Preliminary long-term studies suggest a durable effect on glycemia and improvement in some parameters of beta-cell function. (www.glucagon.com).

78. Dipeptidyl Peptidase-IV Antagonists Sitagliptin and Vildagliptin Sitagliptin and vildagliptin are the first agents in this class to have received FDA approval. Incidence of adverse reactions was reported to be very low in a pooled safety data from 5141 patients. ADA meeting, Chicago, June 2007 . They are indicated as monotherapy and in combination with metformin, thiazolidinediones and insulin. They look to be at least weight neutral.

79. Dipeptidyl Peptidase-IV Antagonists Recent Advances During the last ADA meeting in Chicago, Illinois, 22-26 June 2007, fifty-five presentations addressed 12 different DPP-IV inhibitors and “… more will be seen during the coming months…” Some members seem particularly interesting as saxagliptin (? potent) and alogliptin (long acting… ? Better affecting fasting glucose).

80. Newer Agent Pramlintide Synthetic analog of amylin Suppresses glucagon release, delays gastric emptying & has CNS-mediated anorectic effects An injectable antihyperglycemic, administered in addition to insulin Rapidly absorbed after SC administration, before eating

81. Newer Agent Pramlintide Peak level: 20 minutes Duration: not more than 150 minutes Metabolized & excreted renally Modulates postprandial glucose levels in type 1 & 2 DM SE: hypoglycemia, N/V, & anorexia

82. Summary Insulin resistance and relative insulin secretory defect are key elements of the pathogenesis of type 2 diabetes. GLP-1 deficiency is another key component in diabetic pathophysiology contributing to: - insulin secretory deficit. - excess of plasma glucagon. - postprandial hyperglycemia.

83. Summary Incretin mimetics offer a new approach in the management of type 2 diabetes. Exenatide is the first agent in this class and is administered via injection twice a day. In addition to improving glycemic control, exenatide has the unique benefit of causing weight loss that appears to be prolonged based on initial studies.

84. Summary DPP-IV inhibitors raise GLP-1 levels 2- to 3-fold. They appear to be weight neutral and have a remarkable low incidence of adverse reactions. Sitagliptin ad vildagliptin are the first of the DPP-IV inhibitors to receive FDA approval. these promising new therapies should be undertaken in combination not only with existing oral anti-diabetes medications as indicated, but also with other proven cardiovascular risk-reduction strategies, including lifestyle reduction and pharmacologic therapy, as needed.

85. THANK YOU

86. Insulin Drug Evolution Stage 1 I nsulin was extracted from the glands of cows and pigs. (1920s) Stage 2 Convert pig insulin into human insulin by removing the one amino acid that distinguishes them and replacing it with the human version .

87. Insulin Drug Evolution Stage 3 Insert the human insulin gene into E. coli and culture the recombinant E.coli to produce insulin (trade name = Humulin®). Yeast is also used to produce insulin (trade name = Novolin®) (1987). Recombinant DNA technology has also made it possible to manufacture slightly-modified forms of human insulin that work faster (Humalog® and NovoLog®) or slower (Lantus®) than regular human insulin.