Friday , November 24 2017
Home / Resources / Clinical Gems / ADA/JDRF Type 1 Diabetes Sourcebook, Excerpt #4: Adjunctive Therapies, Part 3 of 3

ADA/JDRF Type 1 Diabetes Sourcebook, Excerpt #4: Adjunctive Therapies, Part 3 of 3

Anne Peters, MD, and Lori Laffel, MD, MPH, Editors
Jane Lee Chiang, MD, Managing Editor


Jeremy Hodson Pettus, MD, and Steven Edelman, MD 

The incretin effect was discovered after experiments found that administration of oral glucose resulted in an increased insulin secretion compared to the same amount of intravenous glucose in healthy controls.42 This effect was eventually ascribed to two hormones produced in the gut, glucagon-like-peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). Both hormones have roles in controlling glucose appearance similar to that of amylin. GLP-1 has been shown to suppress glucagon production, augment glucose-dependent insulin secretion, promote early satiety, and delay gastric emptying.43 Given this physiological abnormality and the beneficial clinical effects, the first GLP-1 analog, exenatide, was approved by the FDA in 2005 for use in T2D….

The incretin effect is somewhat different in T1D patients when compared to T2D. The incretin effect was originally measured by noting the increased release of insulin from an oral glucose load as compared to an IV load. As T1D patients typically do not make insulin, this same effect cannot be demonstrated. However, studies have been done in T1D patients in which levels of GIP and GLP-1 were directly measured after an oral glucose load. These studies have shown that T1D patients seem to make a normal amount of the incretin hormones when compared to controls. However, it was shown that T1D patients had an increased glucagon response to an oral compared to IV load.44 Taken together, these findings make the argument that while T1D patients produce a normal amount of these gut hormones, there still appears to be a dysregulation between the gut and pancreas in which glucagon is not effectively suppressed (see Figure 13.7). This phenomenon raises the possibility that therapeutic intervention with GLP-1 agonists may have beneficial effects in T1D.

Several studies have begun to look specifically at the clinical benefits of GLP-1 agonists in T1D. One such study took 30 patients with T1D and gave them liraglutide once daily over a 4-week period.45 This study broke patients into C-peptide–positive and C-peptide–negative subgroups and compared the effect of the liraglutide with insulin vs. insulin therapy alone. In both C-peptide negative (<0.03 nmol/l) and C-peptide–positive groups (>0.06 nmol/l), the addition of once daily liraglutide showed a trend toward lowered A1C (–0.2% and –0.5%, respectively) at 4 weeks but was not statistically significant. Liraglutide did lead to significantly lower total insulin dose (approximately –0.2 U/kg) and weight loss (–2.3 kg).


Figure 13.7 (a) Levels of GLP-1 are not diminished in T1D. (b) Paradoxical increased glucagon levels in response to oral glucose load compared to IV load in T1D. Source: Hare KJ, Vilsbøll T, Holst JJ, Knop FK: Inappropriate glucagon response after oral compared with isoglycemic intravenous glucose administration in patients with type 1 diabetes. Am J Physiol Endocrinol Metab 298:E832–E837, 2010. Reprinted with permission from the publisher.


Hypoglycemia was not increased with liraglutide but mild and transient nausea was noted at initiation. The degree of insulin dose reduction was found to correlate with underlying β-cell function in that the C-peptide– positive group was able to reduce insulin usage more than the C-peptide–negative group. This study highlights that the clinical benefits of GLP-1 agonists may go beyond glucose dependent insulin secretion as both C-peptide–positive and C-peptide–negative patients trended toward improved glycemic control (see Figure 13.8).45


 In the above-mentioned study, the trial duration of only 4 weeks makes improvements in A1C difficult to detect. In a longer running trial, 14 C-peptide- negative patients were given once-daily liraglutide for one week in addition to insulin therapy. Eight patients then continued on to receive the intervention for 6 months. Over the 6-month period, fasting glucose was reduced, the mean A1C fell (6.5 to 6.1%), total insulin dose was reduced (0.65 to 0.47 U/kg), and there was substantial weight loss (4.5 +/– 1.5 kg) without an increase in hypoglycemia (see Figure 13.9).46


Figure 13.9 Six months of liraglutide lowered A1C and fasting blood glucose while reducing weight, insulin dose, duration of hyperglycemia, and glucose variability. Source: Varanasi A, Bellini N, Rawal D, Vora M, Makdissi A, Dhindsa S, Chaudhuri A, Dandona P: Liraglutide as additional treatment for type 1 diabetes. Eur J Endocrinol 165:77–84, 2011. Reprinted with permission from the publisher.

In summary, GLP-1 agonists have a potential therapeutic role in T1D both in long-standing and new-onset disease. In general, the medication has similar effects as pramlintide by reducing postprandial hyperglycemia while reducing insulin usage and promoting weight loss. An additional advantage of the GLP-1 agonists is the longer dosing intervals. Once-weekly exenatide has been FDA approved for use in T2D patients and even longer formulation including once-monthly and even once/year-infusion devices are being studied. If such formulations could be approved for T1D, the fear of multiple injections would be somewhat alleviated. In the adult patients, longer duration trials and head-to-head comparisons with pramlintide are in process.


Both GLP-1 and GIP are rapidly degraded by the enzyme dipeptidyl peptidase-4 (DPP-4) with circulating half-lives of only several minutes. Therefore, effectively inhibiting this enzyme results in prolonged duration of endogenous GLP-1. Sitagliptin, the first DPP-4 inhibitor, was approved for use in T2D in 2006 and has proven to be a valuable addition in the armamentarium of treating T2D. Like GLP-1 agonists, DPP-4 inhibitors have shown to reduce postprandial hyperglycemia without increased incidence of hypoglycemia.47 They do not show the weight loss that GLP-1 agonists do but carry the benefit of being an oral medication while GLP-1 agonists are exclusively injectables.

One randomized, double-blind trial evaluated the effect of sitagliptin 100 mg/day in 20 patients with T1D. Patients were given sitagliptin 100 mg/day or placebo for 4 weeks and then crossed over. Compared to placebo, sitagliptin was shown to reduce A1C at 4 weeks (–0.27%), reduce postprandial hyperglycemia, and reduce total insulin dose (–0.051 U/kg). No change in weight or hypoglycemic episodes was observed. Limitations were a small sample size, a short trial interval of only 4 weeks, and large placebo effect (see Figure 13.10).48

As with the GLP-1 agonists, larger studies are needed to define the clinical effect of DPP-4 inhibitors in T1D. Additionally, as this class of medication has shown immune modulatory effects, its role in early onset disease is being evaluated. A study funded by the JDRF is underway in which new-onset T1D with disease duration of less than 6 months will be randomized to sitagliptin and lansoprazole (thought to aid β-cell survival by increasing endogenous gastrin levels) vs. placebo with a primary outcome of C-peptide response to a mixed meal tolerance test at baseline compared to at 1 year.


Metformin is an established oral agent that is widely used as a first line agent in the treatment of T2D.49 Its mechanism of action centers around decreasing hepatic glucose production and improving insulin sensitivity. Administration is associated with A1C reduction, weight loss, an improved lipid profile, and decreased levels of inflammation represented by C-reactive protein in T2D. These beneficial effects have led to multiple trials evaluating its use in T1D. Two large reviews have compiled the clinical evidence to date.


Figure 13.10 Sitagliptin reduced mean glucose, A1C, and insulin dose while increasing time spent in euglycemia. Source: Ellis SL, Moser EG, Snell-Bergeon JK, Rodionova AS, Hazenfield RM, Garg SK: Effect of sitagliptin on glucose control in adult patients with type 1 diabetes: a pilot, double-blind, randomized, crossover trial. Diabet Med 28:1176–1181, 2011. Reprinted with permission from the publisher.

In 2009, a Cochrane review was published on the addition of metformin to insulin in adolescents with T1D.50 After searching for any randomized control trial of at least 3-months duration, only two studies could be included. Both trials were 3 months in length and included 30 poorly controlled adolescents (average baseline A1C of around 9%) randomized to placebo vs. metformin up to 2 g/day in addition to insulin. Both studies suggested that metformin therapy led to a reduction in A1C values. There were no comments about lipid profiles or insulin sensitivity although one study noted a 10% reduction in total insulin dosage. Given these findings, the authors conclude that there is some evidence that metformin can improve glycemic control in adolescents but larger studies of longer duration are needed.

A second review was published in 2010 that evaluated the effect of adding metformin to insulin therapy in any patient with T1D.51 The authors ultimately found nine studies that met their search criteria, two of which were also in the Cochrane review noted above. Due to heterogeneity between studies, only five could be included into a formal meta-analysis. In these five studies, metformin had no statistically significant change in A1C but was found to lower insulin dosage by 6.6 U/day. Of note, the largest and longest trial included was of 100 patients randomized to metformin 1g BID vs. placebo and followed for 1 year. In this study, there again was no statistically significant change in A1C, however total daily insulin dose was reduced (–5.7 U/day) and weight loss was observed (–1.74 kg).52

Taking all the data together, metformin appears to have a beneficial effect on insulin sensitivity with reduction in overall insulin requirements and weight. The effect on overall glycemic control is somewhat less clear. As a result, metformin is not currently advocated as an adjunctive therapy for any subgroup of patients with T1D. Clinical data makes it difficult to firmly recommend or refute the use of metformin in an off-label fashion as some patients may benefit from the medication. The group of patients that would theoretically show the most benefit would be poorly controlled diabetics who are overweight and requiring large amounts of insulin.

A large trial entitled “REducing With MetfOrmin Vascular Adverse Lesions in Type 1 Diabetes (REMOVAL)” is currently underway to evaluate the effects of metformin on cardiovascular and metabolic outcomes in T1D. The trial will enroll 500 patients, randomize them to 1g BID of metformin vs. placebo and then follow them for 3 years. The primary outcome will be change in averaged mean common carotid artery intima-media thickness. Multiple other secondary outcomes including A1C and lipid profiles will be evaluated. This study will be the largest and longest running study to date and will hopefully provide a clear answer to the role of metformin in T1D. It is estimated to reach completion in 2016.


Leptin is a 167 amino acid neurohormone produced by adipocytes that plays a key role in the central regulation of appetite, fat and glucose metabolism, and weight. Recombinant leptin (metreleptin) therapy has been shown to have beneficial metabolic effects in patients with lipodystrophy.53 In T1D, mouse studies have shown that administration of leptin alone can restore the health of insulin-deficient animals by eliminating ketoacidosis, effectively making it the only hormone other than insulin with this ability.54,55 Leptin inhibits glucagon production and serves to offset the anabolic effects of insulin on lipids by inhibiting lipo-genesis and cholesterol biosynthesis. A pilot study is underway evaluating the use of adjunctive leptin therapy in T1D. Fifteen patients will be treated with recombinant human leptin and will serve as their own controls. The endpoints will include A1C, energy intake, glucose variability, insulin dose, and others. The study is expected to reach completion in early 2013.


Following cleavage of proinsulin in the islet cells, C-peptide is released along with insulin in equimolar amounts into the portal circulation. C-peptide has long been viewed as an inert byproduct of insulin production, but a recent surge in research has revealed that the peptide has biological activity as its own hormone. Research involving the therapeutic replacement of C-peptide has revealed conflicting results in the T1D and T2D populations. In T2D patients, C-peptide was found to accumulate in carotid artery walls and may promote athrogenic lesions.56 T1D studies, however, have shown more promising results.

A growing amount of evidence in the T1D population has shown that C-peptide replacement can prevent or even reverse diabetic complications in rats, namely neuropathy and nephropathy.57–60 Several human trials have gone on to demonstrate that therapeutic administration has positive effects on diabetic neuropathy as evidenced by improving nerve conduction velocities.61,62 These findings represent a paradigm shift in how we view C-peptide. The protein has long been useful as a surrogate marker for insulin production, and it is well known that preservation of C-peptide status leads to a lower incidence of diabetic complications.32 With evidence of its utility as a therapeutic, it may be the peptide itself that is leading to favorable outcomes. Development of a longer acting subcutaneous injection of C-peptide is underway, which will assist in furthering clinical trials.63


In addition to the therapeutic agents described above, studies have looked into α-glucosidase inhibitors, colesevelam, thiazolidinediones (TZDs), and others.64–66 In general, these studies enrolled very few patients and showed, at best, mild clinical benefits. Therefore, the benefit of these medications is unknown and thus they are not recommended at this time.


Since the discovery of insulin, therapies for T1D have focused on different insulin formulations, meal planning around dosing, correction doses, and other interventions that could be described as insulincentric. However, with the relatively recent discovery of amylin deficiency in T1D, a newfound interest in investigating other potential pathways to treat this patient population has emerged. Furthermore, the proven clinical benefits and FDA approval of pramlintide has shown that adjunctive therapies in T1D can be effectively implemented into clinical practice. This fact has opened the door for an expanded investigation into other therapies. Currently, the incretin-based therapies may have the most promise, as more evidence is accumulating regarding their clinical benefits. Furthermore, with oral administration of the DPP-4 inhibitors and longer acting GLP-1 agonists, patient compliance may increase. Going forward, more clinical trials with larger patient numbers and study durations will need to be done. With some of these already underway, practitioners can expect that the repertoire of medications used to treat patients with T1D will expand in the near future.

  1. Koda JE, Fineman M, Rink TJ, Dailey GE, Muchmore DB, Linarelli LG: Amylin concentrations and glucose control. Lancet 339:1179–1180, 1992
  2. Weyer C, Maggs DG, Young AA, Kolterman OG: Amylin replacement with pramlintide as an adjunct to insulin therapy in type 1 and type 2 diabetes mellitus: a physiological approach toward improved metabolic control. Curr Pharm Des 7:1353–1373, 2001
  3. Kruger DF, Gatcomb PM, Owen SK: Clinical implications of amylin and amylin deficiency. Diabetes Educ 25:389–397; quiz 398, 1999
  4. Koda JE, Fineman MS, Kolterman OG, et al.: 24 hour plasma amylin pro-files are elevated in IGT subjects vs. normal controls [abstract 876]. Diabetes 44 (Suppl. 1):A238, 1995
  5. Fineman MS, Giotta MP, Thompson RG, et al.: Amylin response following Sustacal ingestion is diminished in type II diabetic patients treated with insulin. Diabetologia 39 (Suppl. 1):A149, 1996
  6. Beaumont K, Kenney MA, Young AA, Rink TJ: High affinity amylin binding sites in rat brain. Mol Pharmacol 44:493–497, 1993
  7. Gedulin BR, Rink TJ, Young AA: Dose-response for glucagonostatic effect of amylin in rats. Metabolism 46:67–70, 1997
  8. Silvestre RA, Rodríguez-Gallardo J, Jodka C, Parkes DG, Pittner RA, Young AA, Marco J: Selective amylin inhibition of the glucagon response to arginine is extrinsic to the pancreas. Am J Physiol Endocrinol Metab 280:E443– E449, 2001
  9. Young AA, Gedulin B, Vine W, Percy A, Rink TJ: Gastric emptying is accel-erated in diabetic BB rats and is slowed by subcutaneous injections of amy-lin. Diabetologia 38:642–648, 1995
  10. Young AA, Gedulin BR, Rink TJ: Dose-responses for the slowing of gastric emptying in a rodent model by glucagon-like peptide (7-36) NH2, amylin, cholecystokinin, and other possible regulators of nutrient uptake. Metabolism 45:1–3, 1996
  11. Rushing PA, Hagan MM, Seeley RJ, Lutz TA, Woods SC: Amylin: a novel action in the brain to reduce body weight. Endocrinology 141:850–853, 2000
  12. Rushing PA:,Central amylin signaling and the regulation of energy homeo-stasis. Curr Pharm Des 9:819–825, 2003
  13. Edelman SV, Weyer C: Unresolved challenges with insulin therapy in type 1 and type 2 diabetes: potential benefit of replacing amylin, a second beta-cell hormone. Diabetes Technol Ther 4:175–189, 2002
  14. Rayner CK, Samsom M, Jones KL, Horowitz M: Relationships of upper gastrointestinal motor and sensory function with glycemic control. Diabetes Care 24:371–381, 2001
  15. Kong MF, King P, Macdonald IA, Stubbs TA, Perkins AC, Blackshaw PE, Moyses C, Tattersall RB: Infusion of pramlintide, a human amylin analogue, delays gastric emptying in men with IDDM. Diabetologia 40:82–88, 1997
  16. Kong MF, Stubbs TA, King P, Macdonald IA, Lambourne JE, Blackshaw PE, Perkins AC, Tattersall RB: The effect of single doses of pramlintide on gastric emptying of two meals in men with IDDM. Diabetologia 41:577–583, 1998
  17. Fineman M, Weyer C, Maggs DG, Strobel S, Kolterman OG: The human amylin analog, pramlintide, reduces postprandial hyperglucagonemia in patients with type 2 diabetes mellitus. Horm Metab Res 34:504–508, 2002
  18. Fineman MS, Koda JE, Shen LZ, Strobel SA, Maggs DG, Weyer C, Kolterman OG: The human amylin analog, pramlintide, corrects postprandial hyperglucagonemia in patients with type 1 diabetes. Metabolism 51:636–641, 2002
  19. Amiel SA, Heller SR, Macdonald IA, Schwartz SL, Klaff LJ, Ruggles JA, Weyer C, Kolterman OG, Maggs DG: The effect of pramlintide on hormonal, metabolic or symptomatic responses to insulin-induced hypoglycaemia in patients with type 1 diabetes. Diabetes Obes Metab 7:504–516, 2005
  20. Nyholm B, Møller N, Gravholt CH, Orskov L, Mengel A, Bryan G, Moyses C, Alberti KG, Schmitz O: Acute effects of the human amylin analog AC137 on basal and insulin-stimulated euglycemic and hypoglycemic fuel metabo-lism in patients with insulin-dependent diabetes mellitus. J Clin Endocrinol Metab 81:1083–1089, 1996
  21. Potes CS, Turek VF, Cole RL, Vu C, Roland BL, Roth JD, Riediger T, Lutz TA: Noradrenergic neurons of the area postrema mediate amylin’s hypophagic action. Am J Physiol Regul Integr Comp Physiol 299:R623–R631, 2010
  22. Chapman I, Parker B, Doran S, Feinle-Bisset C, Wishart J, Strobel S, Wang Y, Burns C, Lush C, Weyer C, Horowitz M: Effect of pramlintide on satiety and food intake in obese subjects and subjects with type 2 diabetes. Diabetologia 48:838–848, 2005
  23. Weyer C, Gottlieb A, Kim DD, Lutz K, Schwartz S, Gutierrez M, Wang Y, Ruggles JA, Kolterman OG, Maggs DG: Pramlintide reduces postprandial glucose excursions when added to regular insulin or insulin lispro in subjects with type 1 diabetes: a dose-timing study. Diabetes Care 26:3074–3079, 2003
  24. Levetan C, Want LL, Weyer C, Strobel SA, Crean J, Wang Y, Maggs DG, Kolterman OG, Chandran M, Mudaliar SR, Henry RR: Impact of pramlintide on glucose fluctuations and postprandial glucose, glucagon, and tri-glyceride excursions among patients with type 1 diabetes intensively treated with insulin pumps. Diabetes Care 26:1–8, 2003
  25. Karl D, Philis-Tsimikas A, Darsow T, Lorenzi G, Kellmeyer T, Lutz K, Wang Y, Frias JP: Pramlintide as an adjunct to insulin in patients with type 2 diabetes in a clinical practice setting reduced A1C, postprandial glucose excursions, and weight. Diabetes Technol Ther 9:191–199, 2007
  26. Edelman SV, Darsow T, Frias JP: Pramlintide in the treatment of diabetes. Int J Clin Pract 60:1647–1653, 2006
  27. Maggs DG, Fineman M, Kornstein J, Burrell T, Schwartz S, Wang Y, Rug-gles JA, Kolterman OG, Weyer C: Pramlintide reduces postprandial glucose excursions when added to insulin lispro in subjects with type 2 diabetes: a dose-timing study. Diabetes Metab Res Rev 20:55–60, 2004
  28. Whitehouse F, Kruger DF, Fineman M, Shen L, Ruggles JA, Maggs DG, Weyer C, Kolterman OG: A randomized study and open-label extension evaluating the long-term efficacy of pramlintide as an adjunct to insulin therapy in type 1 diabetes. Diabetes Care 25:724–730, 2002
  29. Ratner RE, Want LL, Fineman MS, Velte MJ, Ruggles JA, Gottlieb A, Weyer C, Kolterman OG: Adjunctive therapy with the amylin analogue pramlintide leads to a combined improvement in glycemic and weight control in insulin-treated subjects with type 2 diabetes. Diabetes Technol Ther 4:51–61, 2002
  30. Hollander PA, Levy P, Fineman MS, Maggs DG, Shen LZ, Strobel SA, Weyer C, Kolterman OG: Pramlintide as an adjunct to insulin therapy improves long-term glycemic and weight control in patients with type 2 diabetes: a 1-year randomized controlled trial. Diabetes Care 26:784–790, 2003
  31. Ratner RE, Dickey R, Fineman M, Maggs DG, Shen L, Strobel SA, Weyer C, Kolterman OG: Amylin replacement with pramlintide as an adjunct to insulin therapy improves long-term glycaemic and weight control in type 1 diabetes mellitus: a 1-year, randomized controlled trial. Diabet Med 21:1204–1212, 2004
  32. Diabetes Control and Complications Trial Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329:977–986, 1993
  33. Edelman S, Garg S, Frias J, Maggs D, Wang Y, Zhang B, Strobel S, Lutz K, Kolterman O: A double-blind, placebo-controlled trial assessing pramlintide treatment in the setting of intensive insulin therapy in type 1 diabetes. Diabetes Care 29:2189–2195, 2006
  34. Kishiyama CM, Burdick PL, Cobry EC, Gage VL, Messer LH, McFann K, Chase HP: A pilot trial of pramlintide home usage in adolescents with type 1 diabetes. Pediatrics 124:1344–1347, 2009
  35. Chase HP, Lutz K, Pencek R, Zhang B, Porter L: Pramlintide lowered glucose excursions and was well-tolerated in adolescents with type 1 diabetes: results from a randomized, single-blind, placebo-controlled, crossover study. J Pediatr 155:369–373, 2009
  36. Hassan K, Heptulla RA: Reducing postprandial hyperglycemia with adjuvant premeal pramlintide and postmeal insulin in children with type 1 diabetes mellitus. Pediatr Diabetes 10:264–268, 2009
  37. Raman VS, Mason KJ, Rodriguez LM, Hassan K, Yu X, Bomgaars L, Heptulla RA: The role of adjunctive exenatide therapy in pediatric type 1 diabetes. Diabetes Care 33:1294–1296, 2010
  38. Hovorka R, Kumareswaran K, Harris J, Allen JM, Elleri D, Xing D, Kollman C, Nodale M, Murphy HR, Dunger DB, Amiel SA, Heller SR, Wilinska ME, Evans ML: Overnight closed loop insulin delivery (artificial pancreas) in adults with type 1 diabetes: crossover randomised controlled studies. BMJ 342:d1855, 2011
  39. Huffman DM, McLean GW, Seagrove MA: Continuous subcutaneous pramlintide infusion therapy in patients with type 1 diabetes: observations from a pilot study. Endocr Pract 15:689–695, 2009
  40. Heptulla RA, Rodriguez LM, Mason KJ, Haymond MW: Twenty-four-hour simultaneous subcutaneous Basal-bolus administration of insulin and amylin in adolescents with type 1 diabetes decreases postprandial hyperglycemia. J Clin Endocrinol Metab 94:1608–1611, 2009
  41. Weyer C, Fineman MS, Strobel S, Shen L, Data J, Kolterman OG, Sylvestri MF: Properties of pramlintide and insulin upon mixing. Am J Health Syst Pharm 62:816–822, 2005
  42. Nauck MA, Homberger E, Siegel EG, Allen RC, Eaton RP, Ebert R, Creutzfeldt W: Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses. J Clin Endocrinol Metab 63:492–498, 1986
  43. Hare KJ, Knop FK: Incretin-based therapy and type 2 diabetes. Vitam Horm 84:389–413, 2010
  44. Hare KJ, Vilsbøll T, Holst JJ, Knop FK: Inappropriate glucagon response after oral compared with isoglycemic intravenous glucose administration in patients with type 1 diabetes. Am J Physiol Endocrinol Metab 298:E832–E837, 2010
  45. Kielgast U, Krarup T, Holst JJ, Madsbad S: Four weeks of treatment with liraglutide reduces insulin dose without loss of glycemic control in type 1 diabetic patients with and without residual beta-cell function. Diabetes Care 34:1463–1468, 2011
  46. Varanasi A, Bellini N, Rawal D, Vora M, Makdissi A, Dhindsa S, Chaudhuri A, Dandona P: Liraglutide as additional treatment for type 1 diabetes. Eur J Endocrinol 165:77–84, 2011
  47. Nauck MA: Incretin-based therapies for type 2 diabetes mellitus: properties, functions, and clinical implications. Am J Med 124 (Suppl. 1):S3–S18, 2011
  48. Ellis SL, Moser EG, Snell-Bergeon JK, Rodionova AS, Hazenfield RM, Garg SK: Effect of sitagliptin on glucose control in adult patients with type 1 diabetes: a pilot, double-blind, randomized, crossover trial. Diabet Med 28:1176–1181, 2011
  49. Standards of medical care in diabetes: 2012. Diabetes Care 35 (Suppl. 1):S11– S63, 2012
  50. Abdelghaffar S, Attia AM: Metformin added to insulin therapy for type 1 diabetes mellitus in adolescents. Cochrane Database Syst Rev CD006691, 2009
  51. Vella S, Buetow L, Royle P, Livingstone S, Colhoun HM, Petrie JR: The use of metformin in type 1 diabetes: a systematic review of efficacy. Diabetologia 53:809–820, 2010
  52. Lund SS, Tarnow L, Astrup AS, Hovind P, Jacobsen PK, Alibegovic AC, Parving I, Pietraszek L, Frandsen M, Rossing P, Parving HH, Vaag AA: Effect of adjunct metformin treatment in patients with type-1 diabetes and persistent inadequate glycaemic control. A randomized study. PLoS One 3:e3363, 2008
  53. Oral EA, Chan JL: Rationale for leptin-replacement therapy for severe lipodystrophy. Endocr Pract 16:324–333, 2010
  54. Fujikawa T, Chuang JC, Sakata I, Ramadori G, Coppari R: Leptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice. Proc Natl Acad Sci U S A 107:17391–17396, 2010
  55. Wang MY, Chen L, Clark GO, Lee Y, Stevens RD, Ilkayeva OR, Wenner BR, Bain JR, Charron MJ, Newgard CB, Unger RH: Leptin therapy in insulin-deficient type I diabetes. Proc Natl Acad Sci U S A 107:4813–4819, 2010
  56. Marx N, Walcher D, Raichle C, Aleksic M, Bach H, Grüb M, Hombach V, Libby P, Zieske A, Homma S, Strong J: C-peptide colocalizes with macrophages in early arteriosclerotic lesions of diabetic subjects and induces monocyte chemotaxis in vitro. Arterioscler Thromb Vasc Biol 24:540–545, 2004
  57. Zhang W, Kamiya H, Ekberg K, Wahren J, Sima AA: C-peptide improves neuropathy in type 1 diabetic BB/Wor rats. Diabetes Metab Res Rev 23:63– 70, 2007
  58. Sima AA, Zhang W, Sugimoto K, Henry D, Li Z, Wahren J, Grunberger G: C-peptide prevents and improves chronic type I diabetic polyneuropathy in the BB/Wor rat. Diabetologia 44:889–897, 2001
  59. Samnegard B, Jacobson SH, Jaremko G, Johansson BL, Ekberg K, Isaks-son B, Eriksson L, Wahren J, Sjöquist M: C-peptide prevents glomerular hypertrophy and mesangial matrix expansion in diabetic rats. Nephrol Dial Transplant 20:532–538, 2005
  60. Maezawa Y, Yokote K, Sonezaki K, Fujimoto M, Kobayashi K, Kawamura H, Tokuyama T, Takemoto M, Ueda S, Kuwaki T, Mori S, Wahren J, Saito Y: Influence of C-peptide on early glomerular changes in diabetic mice. Diabetes Metab Res Rev 22:313–322, 2006
  61. Ekberg K, Brismar T, Johansson BL, Lindström P, Juntti-Berggren L, Nor-rby A, Berne C, Arnqvist HJ, Bolinder J, Wahren J: C-peptide replacement therapy and sensory nerve function in type 1 diabetic neuropathy. Diabetes Care 30:71–76, 2007
  62. Ekberg K, Brismar T, Johansson BL, Jonsson B, Lindström P, Wahren J: Amelioration of sensory nerve dysfunction by C-Peptide in patients with type 1 diabetes. Diabetes 52:536–541, 2003
  63. Wahren J, Kallas A, Sima AA: The clinical potential of C-Peptide replacement in type 1 diabetes. Diabetes 61:761–772, 2012
  64. Garg SK, Ritchie PJ, Moser EG, Snell-Bergeon JK, Freson BJ, Hazenfield RM: Effects of colesevelam on LDL-C, A1c and GLP-1 levels in patients with type 1 diabetes: a pilot randomized double-blind trial. Diabetes Obes Metab 13:137–143, 2011
  65. Rabasa-Lhoret R, Burelle Y, Ducros F, Bourque J, Lavoie C, Massicotte D, Péronnet F, Chiasson JL: Use of an alpha-glucosidase inhibitor to maintain glucose homoeostasis during postprandial exercise in intensively treated type 1 diabetic subjects. Diabet Med 18:739–744, 2001
  66. Kawano Y, Irie J, Nakatani H, Yamada S: Pioglitazone might prevent the progression of slowly progressive type 1 diabetes. Intern Med 48:1037–1039, 2009


Used with permission by the American Diabetes Association. Copyright © 2013 American Diabetes Association.

Please note: We are proud to have Dr. Anne Peters as a member of our Advisory Board member for Diabetes In Control, Inc.


T1-diabetes-sourcebookIf you would like to purchase the full text of The Type 1 Diabetes Sourcebook, Anne Peters, MD, and Lori Laffel, MD, MPH, editors, and Jane Lee Chiang, MD, managing editor, just follow this link.