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Insulin: A new era for an old hormone
Pharmacological Research 61 (2010) 1–4
Contents lists available at ScienceDirect
Pharmacological Research journal homepage: www.elsevier.com/locate/yphrs
Perspective
Insulin: A new era for an old hormone夽 Vladimir Sabetsky a , Jonas Ekblom a,b,∗ a b
Bows Pharmaceuticals AG, Bahnhofstrasse 7, CH-6301 Zug, Switzerland Department of Neuroscience, Uppsala University, BMC, Box 593, SE-751 24 Uppsala, Sweden
a r t i c l e
i n f o
Article history: Received 27 July 2009 Accepted 31 July 2009 Keywords: Hepatic Hyperglycemia Hypoglycemia Insulin resistance Peroral Portal
a b s t r a c t All forms of diabetes have been treatable since insulin became medically available in 1921. While insulin alone produces a substantial reduction in blood-glucose levels and is thus the mainstay of treating type-1 diabetes, today’s peroral agents used in treating type-2 diabetes struggle to achieve satisfactory clinical results in the absence of endogenous or exogeneous insulin. Emerging evidence suggests that insulin may not only produce symptomatic effects; recent data suggest that insulin may stimulate -cell recovery. In fact, short-term insulin therapy appears to result in long-term improvement in blood-glucose control, especially when administered in early stages of type-2 diabetes. During the last decade the pharmaceutical industry has largely failed to introduce new agents that can fundamentally improve the course of diabetes and the safety of artificial insulin analogs is undergoing thorough investigation. In contrast, new delivery approaches that present natural recombinant insulin to the enterohepatic circulation holds the promise of radically improving the treatment of type-2 diabetes. © 2010 Elsevier Ltd. All rights reserved.
Contents 1. 2. 3. 4.
5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Insulin and the pathogenesis of type-2 diabetes mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The therapeutic value of insulin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Why are new delivery forms of insulin needed? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Disadvantages of existing insulin products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Issues in development of new chemical entities for treatment of diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. The advantage of portal insulin delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Industry efforts in the field of oral insulin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Diabetes is one of the costliest health problems in the world; indeed costs continue to spiral in the face of widespread increasing prevalence of obesity. The significance of the epidemiological burden of diabetes lies in the complexity of this metabolic
Abbreviations: OAD, oral antidiabetic drugs; T1D, type-1 diabetes mellitus; T2D, type-2 diabetes mellitus; HbA1C , hemoglobin A1C . 夽 Perspective articles contain the personal views of the authors who, as experts, reflect on the direction of future research in their field. ∗ Corresponding author at: Bahnhofstrasse 7, CH-6301 Zug, Switzerland. E-mail addresses: [email protected] (V. Sabetsky), [email protected] (J. Ekblom). 1043-6618/$ – see front matter © 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.phrs.2009.07.010
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disease which may, if left untreated or not appropriately treated, develop into complications, many of which are life-threatening and very costly to treat. In the developed world, diabetes is one of the main causes of cardiovascular disease including heart attacks and strokes, the most common cause of adult blindness in the nonelderly, the leading cause of non-traumatic amputation in adults, and diabetic nephropathy is the main driver of renal dialysis [1]. In the US alone, treatment of patients with diabetes and diabetic complications is estimated to cost over 100 billion dollars each year [2,3]. In fact, the International Diabetes Federation estimates direct costs of diabetes to be approximately 6% of the total health budget of economically developed countries. Consequently, the need for new options to treat diabetes and specifically type-2 diabetes (T2D) at early stages of the disease is increasing at tremendous speed.
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The importance of good glycemic control to reduce the risk of vascular complications of hyperglycemia is well established [4]. However, T2D is a progressive disease, and the need for increasing the intensity of treatment to maintain glycemic control is an indicator of that progression. A variety of new oral antidiabetic drugs (OAD) have emerged for the treatment of T2D—dipeptidyl peptidase-4 inhibitors, glucagon-like peptide 1 analogs, thiazolidinediones, glinides, selective sodium glucose cotransporter 2 inhibitors, and several other unique agents now in development. Despite recent progress, the management of T2D with OAD alone appears to be suboptimal for many patients [5]. Ultimately, most patients will require insulin therapy, although insulin is still all too often thought of as “last resort” or “endstage” therapy [6]. This and other misperceptions frequently limit the early initiation of insulin therapy, even among patients to whom OAD are no longer adequate. Many patients with a high pretreatment hemoglobin A1C (HbA1c ) are not adequately controlled by a single oral agent even at high dose suggesting that earlier, more aggressive treatment in primary care is required [7]. Insulin is the only agent of “universal” value for treatment of diabetes mellitus (T1D and T2D). In reality, current classes of OAD are truly effective only in combination with insulin produced by -cells (endogeneous insulin) or administered by injection or other delivery systems (exogeneous insulin), or combination of both—endogeneous and exogeneous. Insulin can be used in therapy of diabetes without any other drugs but not vice versa.
studies, insulin therapy greatly improved insulin secretion, presumably by reducing hyperglycemia [11–14]. There is research evidence that insulin protects islets from apoptosis and that insulin may even increase -cell regeneration [15,16]. Interestingly, shortterm insulin therapy appears to result in long-term improvement in blood-glucose control, especially when administered in the earliest stages of diabetes [11–14,17,18]. For example, in a recent study by Chen et al. [11] it was shown that in newly diagnosed T2D with elevated fasting glucose levels, a 2–3-week course of intensive insulin therapy can successfully lay a foundation for prolonged good glycemic control. The ease with which normoglycemia is achieved on insulin may predict those patients who can later succeed in controlling glucose levels with attention to diet alone. Based on these and similar observations from other investigators, some diabetes experts have advocated initiating intensive insulin therapy early in the course of T2D, or immediately after a diet and exercise regimen fails, in an effort to preserve remaining -cell function and improve long-term glycemic control [14,19]. Finally, insulin also presents some advantages from a pharmacodynamic stand-point as compared with OAD. Unlike the other blood-glucose-lowering medications, insulin has an exceptionally wide therapeutic window, i.e., there is no known maximum dose of insulin beyond which a therapeutic effect will not be relevant. It is noteworthy that relatively large doses of insulin compared with those required to treat T1D, may be necessary to overcome the insulin resistance of T2D and lower HbA1C to the target level.
2. Insulin and the pathogenesis of type-2 diabetes mellitus
4. Why are new delivery forms of insulin needed?
The advent of genome-wide association screening has uncovered spectacular new findings in regards to loci associated with T2D. Until recently, the predominant view of the scientific community was that genes affecting insulin sensitivity represented the primary genetic factors in T2D. In the light of emerging genetic findings, this is now being reconsidered. In fact, most of the T2D gene loci identified during the last few years point towards a susceptibility in the molecular biology of insulin secretion rather than insulin sensitivity as a genetic basis for the disease [8]. There is a progressive deterioration in -cell function and mass in type 2 diabetics [9]. For example, in a study by Butler et al. [10] it was found that islet function was about 50% of normal at the time of diagnosis, and a reduction in -cell mass of about 60% was shown at necropsy. Experimental research strongly suggests that the reduction of -cell mass is attributable to accelerated apoptosis. It has been generally assumed that major factors for progressive loss of -cell function and mass include glucotoxicity, lipotoxicity, proinflammatory cytokines, and islet cell amyloidosis. Moreover, it is now recognized that the -cell failure occurs much earlier and is more severe than previously thought [9,10]. Interestingly, impaired -cell function and possibly -cell mass appear to be reversible, particularly at early stages of the disease where the limiting threshold for reversibility of decreased -cell mass has probably not been passed. Among the interventions that have been postulated for protection and “rejuvenation” of -cells, short term intensive insulin therapy in newly diagnosed T2D has shown to improve -cell function, usually leading to a period of remission [7,11,12].
The clinical course of T2D is characterized by defects in both insulin secretion and insulin action. The defect in insulin secretion seems to be progressive; newly diagnosed patients in the U.K. Prospective Diabetes Study [20] had 50% of normal insulin secretion upon initial diagnosis, but this had declined to <25% of normal insulin secretion 6 years after diagnosis. The results of multiple investigations strongly suggest that good glycemic control in T2D often requires insulin supplementation therapy, for a review see De Witt and Hirsch [21]. Unfortunately, many patients with T2D who could benefit from insulin therapy do not receive it or do not receive it in a timely manner [22]. Part of this gap appears to be attributable to reluctance to taking insulin among patients and resistance to prescribing insulin among health care providers. This resistance is based on a variety of factors, primarily beliefs and perceptions regarding diabetes and its treatment, the nature and consequences of insulin therapy, and how others would regard insulin therapy [23]. For example, T2D patients tend to be older and more difficult to train on testing their own blood-glucose levels and to self-administer injectable insulin.
3. The therapeutic value of insulin The need for insulin depends upon the balance between insulin secretion and insulin resistance. Mounting evidence suggests that insulin therapy not only produces symptomatic improvements, but also that insulin treatment can help correct the underlying pathogenetic mechanisms responsible for type 2 diabetes, namely, insulin resistance and impaired insulin secretion. In a number of
4.1. Disadvantages of existing insulin products Although insulin is the most effective therapy for reducing blood-glucose levels, the current injectable forms of insulin present several drawbacks [24]. The need for multiple injections daily is a substantial disadvantage. This is due to a number of factors including needle phobia, non-physiological delivery to the wrong target tissues, poor pharmacodynamics and often non-ideal treatment initiation. In regards to adverse effects, the risk of hypoglycemic episodes and weight gain represent concerns for injection therapy with insulin. Moreover, the safety of long-acting insulin analogs has recently been questioned. A number of recent studies suggest that these long-acting synthetic chemical entities may produce an increased risk of breast cancer. As reviewed by Smith and Gale [25] a number of retrospective studies submitted in 2008 and 2009 suggest that
V. Sabetsky, J. Ekblom / Pharmacological Research 61 (2010) 1–4
use of insulin glargine is, after adjustment for dose, associated with a possible increase in tumor risk in humans. Interpretation of this analysis proved controversial, but the implications are serious. In the case of glargin, the most commonly used long-acting insulin analog, the question has been raised as to whether this insulin analogue may have specific growth promoting potential, which could be expressed as tumor-promoting activity in patients [26]. 4.2. Issues in development of new chemical entities for treatment of diabetes By many accounts, the pharmaceutical industry is experiencing a severe decline in research productivity. More and more capital is being invested in research and development, but the rate at which new drugs are introduced to the market is failing to keep pace. According to the FDA, new compounds entering Phase I development today have only an 8% chance of reaching the market versus a 14% chance 15 years ago. And the Phase III failure rate has risen to 50% versus 20% just ten years ago [27]. This issue is particularly apparent in the field of diabetes. Moreover, in 2008, FDA introduced a new guideline for clinical development of anti-diabetes agents [28]. This new guideline stipulates a minimum number of test subjects to be enrolled and a minimum duration of the evaluation period on pivotal clinical trials. The reason for the high safety demands of novel anti-diabetes treatments involve (i) a rapidly increasing size of the target population, (ii) a decrease in the average age at diagnosis and (iii) the life-long requirement for therapy of subjects once obtaining the diagnosis. Furthermore, in 2008, concern over reports that link diabetes drugs to cardiac problems, U.S. drug regulators today ask diabetesdrug makers for more safety data. These requests for additional data could delay new product approvals by years and add millions of dollars to development and post-market commitment costs [29]. 4.3. The advantage of portal insulin delivery The basic goal of tight control of blood-glucose using intensive insulin therapy is to mimic insulin secretion by the normal pancreas. Today, this involves designing a regimen that includes a long-acting or intermediate-acting insulin preparations that approximates basal insulin secretion (i.e., the small amount of insulin the pancreas secretes continuously) and a short-acting insulin preparation that is administered before mealtimes and mimics the extra insulin the pancreas secretes to handle the postprandial rise in blood-glucose levels. The advent of insulin pumps is one more recent approach to fine-tuning delivery in order to gain greater control. There have been a number of pharmaceutical approaches to developing a non-invasive delivery route for insulin, most of them topical (e.g. patches) or inhalation. These share the same weakness as injectable insulin: the delivered protein passes first into the peripheral circulation and only thereafter, in much diluted form, into the liver. Thus topically and subcutaneously administered insulin result in fat and muscle being exposed to higher insulin levels than the liver. This is in contrast to endogeneous insulin which is delivered from the pancreas into the portal system and the liver. Oral delivery would share this advantage. The emergence of new non-invasive delivery technologies that allows administration of insulin through the portal vein instill hope for therapeutic breakthrough. For example, reports on portal delivery of insulin from islet grafts in the portal vein demonstrate that portal delivery of insulin is important in maintenance of normal whole-body insulin sensitivity [30,31]. Moreover, the advantages of portal insulin delivery are intensively discussed in the publications
3
dedicated to development of oral insulin delivery systems [32]. Oral insulin administration better mimics endogeneous production and is more convenient for the patient than conventional subcutaneous insulin administration. Given orally and delivered to the portal vein normal vein/arterial insulin distribution would be restored. In addition, portal delivery of insulin may present advantages in terms of lower risk for carcinogenesis. Since insulin after absorption undergoes a substantial first pass clearance, only a small fraction of the administered drug will reach the extrahepatic circulation. After oral delivery, the absorbed insulin will predominantly exert its effect in the liver where it also is metabolized. Consequently, upon oral delivery of insulin, a lower continuous extrahepatic insulin tone is predicted to occur which may be advantageous in the light of insulin’s mitogenic properties. 4.4. Industry efforts in the field of oral insulin The various challenges associated with the production of a reliable insulin formulation for peroral delivery includes (i) maintaining storage stability of the active protein, (ii) avoiding enzymatic degradation in the gastrointestinal tract and (iii) overcoming poor spontaneous insulin permeability through the gastrointestinal system. Despite the multiple technical challenges several companies have announced initiatives in this direction, including Apollo Life Sciences, Biocon, Diabetology Ltd., Emisphere, Oramed and Orin Pharmaceuticals AG. One may speculate that the administration of human recombinant insulin without chemical modifications or co-formulation with any new chemical entity may provide advantages in terms of development risks. For example, three biotechnology companies—Diabetology Ltd., Oramed and Orin Pharmaceuticals have indicated progress in this respect and have in fact reached the stage of Phase II clinical trials of oral insulin preparations. Diabetology Ltd. has developed a delivery system which significantly increases the absorption of peptides, proteins and other macromolecules across the intestinal wall when delivered orally without any chemical modification of the active compounds. The delivery system is based on a simple mixture of components consisting of excipients with absorption-enhancing activities. Results were recently announced from 10-day repeat-dosing of CapsulinTM oral insulin in patients with T2D [33]. The study showed that CapsulinTM was able to improve glycemic control throughout the day, including mealtimes, with reduced glucose fluctuations and postprandial glucose rises. These observations were associated with significant improvements in HbA1C , weight and triglycerides between pre-study screen and study close. At the same time CapsulinTM was found to be safe and well tolerated with no serious adverse events and no hypoglycemia occurring. Another company, Oramed, has announced the completion of a Phase IIa stage clinical trial of ORMD 0801, which is a capsule formulation of insulin that incorporates adjuvants. These adjuvants are intended to protect the active protein while in transit through the harsh chemical environment of the gastrointestinal tract and promote its transport across the intestinal mucosa. ORMD 0801 was well tolerated by all patients and in two thirds of the subjects analyzed, statistically significant reductions in glucose as well as C-peptide were observed. Finally, Orin Pharmaceuticals AG is preparing a Phase II clinical trial in T2D for its oral insulin preparation. The company has developed a proprietary formulation consisting of dextran matrix for oral delivery of insulin. Being included in the dextran matrix, insulin is protected against proteolytic degradation in the gastric ventricle. Subsequently, the dextran matrix is degraded by endogenous enzymes in the mucosa of the small intestine resulting in targeted delivery at a site where insulin is spontaneously absorbed at an optimal rate. Early clinical testing in T2D patients has demonstrated absorption at clinically useful levels.
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Treatment of early stage T2D is going to require an unprecedented demonstration of safety for the patient. In the future, subjects will start treatment at earlier stages (and ages) perhaps without any other ailments. Moreover, subjects with T2D are likely to live longer and need to maintain the therapy for extended periods of time, perhaps for decades. Consequently, insulin, which is a naturally occurring hormone, will present advantages as compared to new chemical entities. In summary, a number of industry programs are currently evaluating non-invasive delivery approaches that more closely mimics the natural exposure and action of insulin as well as being more convenient and safe to the patient. 5. Concluding remarks Insulin is the most effective medicine at lowering hyperglycemia which can in turn decrease any level of elevated HbA1C to, or close to, the therapeutic goal. The effectiveness, cost, and, apart from hypoglycaemia, lack of severe side effects make insulin the ideal treatment for diabetes mellitus. New evidence point to a curative value of early insulin administration. Early introduction of insulin in pre-diabetics may in fact delay the onset of T2D. Non-invasive delivery approaches that more closely mimic the natural exposure route for the hormone would present substantial advantages over existing diabetes drugs. Several clinical studies are ongoing with the objective of assessing the therapeutic potential of oral delivery technologies for insulin. While the pharmaceutical industry has largely failed to develop new agents that can fundamentally improve the disease course of T2D, new delivery approaches of insulin that present insulin to the enterohepatic circulation offers promise to fundamentally change the pharmacological treatment of diabetes mellitus. Acknowledgement The authors would like to thank Dr. Anthony Wild for advice and comments on the manuscript. References [1] Meetoo D, McGovern P, Safadi R. An epidemiological overview of diabetes across the world. Br J Nurs 2007;16:1002–7. [2] Ray JA, Valentine WJ, Secnik K, Oglesby AK, Cordony A, Gordois A, et al. Review of the cost of diabetes complications in Australia, Canada, France, Germany, Italy and Spain. Curr Med Res Opin 2005;21:1617–29. [3] Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 2004;27:1047–53. [4] Mellbin LG, Malmberg K, Norhammar A, Wedel H, Rydén L, DIGAMI 2 Investigators. The impact of glucose lowering treatment on long-term prognosis in patients with type 2 diabetes and myocardial infarction: a report from the DIGAMI 2 trial. Eur Heart J 2008;29:166–76. [5] Calvert MJ, McManus RJ, Freemantle N. The management of people with type 2 diabetes with hypoglycaemic agents in primary care: retrospective cohort study. Fam Practice 2007;24:224–9. [6] Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of longterm complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977–86. [7] Niswender K. Early and aggressive initiation of insulin therapy for type 2 diabetes: what is the evidence? Clin Diabetes 2009;27:60–8. [8] Perry JR, Frayling TM. New gene variants alter type 2 diabetes risk predominantly through reduced beta-cell function. Curr Opin Clin Nutr Metab Care 2008;11:371–7.
[9] Wajchenberg BL. -Cell failure in diabetes and preservation by clinical treatment. Endocr Rev 2007;28:187–218. [10] Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. ß-Cell deficit and increased ß-cell apoptosis in humans with type 2 diabetes. Diabetes 2003;52:102–10. [11] Chen HS, Wu TE, Jap TS, Hsiao LC, Lee SH, Lin HD. Beneficial effects of insulin on glycemic control and beta-cell function in newly diagnosed type 2 diabetes with severe hyperglycemia after short-term intensive insulin therapy. Diabetes Care 2008;31:1927–32. [12] Ryan EA, Imes S, Wallace C. Short-term intensive insulin therapy in newly diagnosed type 2 diabetes. Diabetes Care 2004;27:1028–32. [13] Della Casa L, del Rio G, Glaser B, Cerasi E. Effect of 6-month gliclazide treatment on insulin release and sensitivity to endogenous insulin in NIDDM: role of initial continuous subcutaneous insulin infusion-induced normoglycemia. Am J Med 1991;90:37S–45S. [14] Ilkova H, Glaser B, Tunckale A, Bagriac¸ik N, Cerasi E. Induction of long-term glycemic control in newly diagnosed type 2 diabetic patients by transient intensive insulin treatment. Diabetes Care 1997;20:1353–6. [15] Kulkarni RN. Receptors for insulin and insulin-like growth factor-1 and insulin receptor substrate-1 mediate pathways that regulate islet function. Biochem Soc Trans 2002;30:317–22. [16] Beith JL, Alejandro EU, Johnson JD. Insulin stimulates primary beta-cell proliferation via Raf-1 kinase. Endocrinology 2008;149:2251–60. [17] Foley JE, Kashiwagi A, Verso MA, Reaven G, Andrews J. Improvement in in vitro insulin action after one month of insulin therapy in obese noninsulin-dependent diabetics. Measurements of glucose transport and metabolism, insulin binding, and lipolysis in isolated adipocytes. J Clin Invest 1983;72:1901–9. [18] Skyler JS. Insulin therapy in type II diabetes: who needs it, how much of it, and for how long? Postgrad Med 1997;101:85–96. [19] Fontbomme AM, Eschwege EM. Insulin and cardiovascular disease: Paris Prospective Study. Diabetes Care 1991;14:461–9. [20] UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837–53. [21] De Witt DE, Hirsch IB. Outpatient insulin therapy in type 1 and type 2 diabetes mellitus: a scientific review. JAMA 2003;289:2254–64; Dailey GE. Early insulin: an important therapeutic strategy. Diabetes Care 2005;28:220–1. [22] Peyrot M. Psychological insulin resistance: overcoming barriers to insulin therapy. Practical Diabetol 2004;23:6–12. [23] Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2009;32:193–203. [24] Peyrot M, Rubin RR, Lauritzen T, Skovlund SE, Snoek FJ, Matthews DR, et al. Resistance to insulin therapy among patients and providers: results of the cross-national Diabetes Attitudes, Wishes, and Needs (DAWN) study. Diabetes Care 2005;28:2673–9. [25] Smith U, Gale EAM. Does diabetes therapy influence the risk of cancer? Diabetologia 2009;52:1441–5. [26] Kurtzhals P, Schäffer L, Sørensen A, Kristensen C, Jonassen I, Schmid C, et al. Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. Diabetes 2000;49:999–1005. [27] Tempio JS. Squeeze play 2008: price pressure and declining R&D productivity. Pharmaceut Proc 2008;7:121–31. [28] Guidance for industry: diabetes mellitus: developing drugs and therapeutic biologics for treatment and prevention. Food and Drug Administration, Center for Drug Evaluation and Research (CDER). February 2008. [29] Guidance for industry: diabetes mellitus—evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. Food and Drug Administration, Center for Drug Evaluation and Research (CDER). December 2008. [30] Katsuragi I, Okeda T, Yoshimatsu H, Utsunomiya N, Ina K, Sakata T. Transplantation of normal islets into the portal vein of Otsuka Long Evans Tokushima Fatty Rats prevents diabetic progression. Exp Biol Med 2001;226: 681–5. [31] Guan J, Zucker PF, Behme MT, Zhong R, Atkison P, Dupre J. Insulin resistance prevented by portal delivery of insulin in rats with renal subcapsular islet grafts. Diabetes 1997;46:372–8. [32] Arbit E, Kidron M. Oral insulin: the rational for this approach and current developments. J Diabetes Sci Technol 2009;3:562–7. [33] Diabetology Ltd. corporate web site. Repeat dosing data for Capsulin phase II in type 2 diabetes presented at the EASD Conference in Rome, Sep 2008. http://www.diabetology.co.uk/EASD Rome Ph2 release 0908.htm.
Contents lists available at ScienceDirect
Pharmacological Research journal homepage: www.elsevier.com/locate/yphrs
Perspective
Insulin: A new era for an old hormone夽 Vladimir Sabetsky a , Jonas Ekblom a,b,∗ a b
Bows Pharmaceuticals AG, Bahnhofstrasse 7, CH-6301 Zug, Switzerland Department of Neuroscience, Uppsala University, BMC, Box 593, SE-751 24 Uppsala, Sweden
a r t i c l e
i n f o
Article history: Received 27 July 2009 Accepted 31 July 2009 Keywords: Hepatic Hyperglycemia Hypoglycemia Insulin resistance Peroral Portal
a b s t r a c t All forms of diabetes have been treatable since insulin became medically available in 1921. While insulin alone produces a substantial reduction in blood-glucose levels and is thus the mainstay of treating type-1 diabetes, today’s peroral agents used in treating type-2 diabetes struggle to achieve satisfactory clinical results in the absence of endogenous or exogeneous insulin. Emerging evidence suggests that insulin may not only produce symptomatic effects; recent data suggest that insulin may stimulate -cell recovery. In fact, short-term insulin therapy appears to result in long-term improvement in blood-glucose control, especially when administered in early stages of type-2 diabetes. During the last decade the pharmaceutical industry has largely failed to introduce new agents that can fundamentally improve the course of diabetes and the safety of artificial insulin analogs is undergoing thorough investigation. In contrast, new delivery approaches that present natural recombinant insulin to the enterohepatic circulation holds the promise of radically improving the treatment of type-2 diabetes. © 2010 Elsevier Ltd. All rights reserved.
Contents 1. 2. 3. 4.
5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Insulin and the pathogenesis of type-2 diabetes mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The therapeutic value of insulin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Why are new delivery forms of insulin needed? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Disadvantages of existing insulin products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Issues in development of new chemical entities for treatment of diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. The advantage of portal insulin delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Industry efforts in the field of oral insulin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Diabetes is one of the costliest health problems in the world; indeed costs continue to spiral in the face of widespread increasing prevalence of obesity. The significance of the epidemiological burden of diabetes lies in the complexity of this metabolic
Abbreviations: OAD, oral antidiabetic drugs; T1D, type-1 diabetes mellitus; T2D, type-2 diabetes mellitus; HbA1C , hemoglobin A1C . 夽 Perspective articles contain the personal views of the authors who, as experts, reflect on the direction of future research in their field. ∗ Corresponding author at: Bahnhofstrasse 7, CH-6301 Zug, Switzerland. E-mail addresses: [email protected] (V. Sabetsky), [email protected] (J. Ekblom). 1043-6618/$ – see front matter © 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.phrs.2009.07.010
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disease which may, if left untreated or not appropriately treated, develop into complications, many of which are life-threatening and very costly to treat. In the developed world, diabetes is one of the main causes of cardiovascular disease including heart attacks and strokes, the most common cause of adult blindness in the nonelderly, the leading cause of non-traumatic amputation in adults, and diabetic nephropathy is the main driver of renal dialysis [1]. In the US alone, treatment of patients with diabetes and diabetic complications is estimated to cost over 100 billion dollars each year [2,3]. In fact, the International Diabetes Federation estimates direct costs of diabetes to be approximately 6% of the total health budget of economically developed countries. Consequently, the need for new options to treat diabetes and specifically type-2 diabetes (T2D) at early stages of the disease is increasing at tremendous speed.
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The importance of good glycemic control to reduce the risk of vascular complications of hyperglycemia is well established [4]. However, T2D is a progressive disease, and the need for increasing the intensity of treatment to maintain glycemic control is an indicator of that progression. A variety of new oral antidiabetic drugs (OAD) have emerged for the treatment of T2D—dipeptidyl peptidase-4 inhibitors, glucagon-like peptide 1 analogs, thiazolidinediones, glinides, selective sodium glucose cotransporter 2 inhibitors, and several other unique agents now in development. Despite recent progress, the management of T2D with OAD alone appears to be suboptimal for many patients [5]. Ultimately, most patients will require insulin therapy, although insulin is still all too often thought of as “last resort” or “endstage” therapy [6]. This and other misperceptions frequently limit the early initiation of insulin therapy, even among patients to whom OAD are no longer adequate. Many patients with a high pretreatment hemoglobin A1C (HbA1c ) are not adequately controlled by a single oral agent even at high dose suggesting that earlier, more aggressive treatment in primary care is required [7]. Insulin is the only agent of “universal” value for treatment of diabetes mellitus (T1D and T2D). In reality, current classes of OAD are truly effective only in combination with insulin produced by -cells (endogeneous insulin) or administered by injection or other delivery systems (exogeneous insulin), or combination of both—endogeneous and exogeneous. Insulin can be used in therapy of diabetes without any other drugs but not vice versa.
studies, insulin therapy greatly improved insulin secretion, presumably by reducing hyperglycemia [11–14]. There is research evidence that insulin protects islets from apoptosis and that insulin may even increase -cell regeneration [15,16]. Interestingly, shortterm insulin therapy appears to result in long-term improvement in blood-glucose control, especially when administered in the earliest stages of diabetes [11–14,17,18]. For example, in a recent study by Chen et al. [11] it was shown that in newly diagnosed T2D with elevated fasting glucose levels, a 2–3-week course of intensive insulin therapy can successfully lay a foundation for prolonged good glycemic control. The ease with which normoglycemia is achieved on insulin may predict those patients who can later succeed in controlling glucose levels with attention to diet alone. Based on these and similar observations from other investigators, some diabetes experts have advocated initiating intensive insulin therapy early in the course of T2D, or immediately after a diet and exercise regimen fails, in an effort to preserve remaining -cell function and improve long-term glycemic control [14,19]. Finally, insulin also presents some advantages from a pharmacodynamic stand-point as compared with OAD. Unlike the other blood-glucose-lowering medications, insulin has an exceptionally wide therapeutic window, i.e., there is no known maximum dose of insulin beyond which a therapeutic effect will not be relevant. It is noteworthy that relatively large doses of insulin compared with those required to treat T1D, may be necessary to overcome the insulin resistance of T2D and lower HbA1C to the target level.
2. Insulin and the pathogenesis of type-2 diabetes mellitus
4. Why are new delivery forms of insulin needed?
The advent of genome-wide association screening has uncovered spectacular new findings in regards to loci associated with T2D. Until recently, the predominant view of the scientific community was that genes affecting insulin sensitivity represented the primary genetic factors in T2D. In the light of emerging genetic findings, this is now being reconsidered. In fact, most of the T2D gene loci identified during the last few years point towards a susceptibility in the molecular biology of insulin secretion rather than insulin sensitivity as a genetic basis for the disease [8]. There is a progressive deterioration in -cell function and mass in type 2 diabetics [9]. For example, in a study by Butler et al. [10] it was found that islet function was about 50% of normal at the time of diagnosis, and a reduction in -cell mass of about 60% was shown at necropsy. Experimental research strongly suggests that the reduction of -cell mass is attributable to accelerated apoptosis. It has been generally assumed that major factors for progressive loss of -cell function and mass include glucotoxicity, lipotoxicity, proinflammatory cytokines, and islet cell amyloidosis. Moreover, it is now recognized that the -cell failure occurs much earlier and is more severe than previously thought [9,10]. Interestingly, impaired -cell function and possibly -cell mass appear to be reversible, particularly at early stages of the disease where the limiting threshold for reversibility of decreased -cell mass has probably not been passed. Among the interventions that have been postulated for protection and “rejuvenation” of -cells, short term intensive insulin therapy in newly diagnosed T2D has shown to improve -cell function, usually leading to a period of remission [7,11,12].
The clinical course of T2D is characterized by defects in both insulin secretion and insulin action. The defect in insulin secretion seems to be progressive; newly diagnosed patients in the U.K. Prospective Diabetes Study [20] had 50% of normal insulin secretion upon initial diagnosis, but this had declined to <25% of normal insulin secretion 6 years after diagnosis. The results of multiple investigations strongly suggest that good glycemic control in T2D often requires insulin supplementation therapy, for a review see De Witt and Hirsch [21]. Unfortunately, many patients with T2D who could benefit from insulin therapy do not receive it or do not receive it in a timely manner [22]. Part of this gap appears to be attributable to reluctance to taking insulin among patients and resistance to prescribing insulin among health care providers. This resistance is based on a variety of factors, primarily beliefs and perceptions regarding diabetes and its treatment, the nature and consequences of insulin therapy, and how others would regard insulin therapy [23]. For example, T2D patients tend to be older and more difficult to train on testing their own blood-glucose levels and to self-administer injectable insulin.
3. The therapeutic value of insulin The need for insulin depends upon the balance between insulin secretion and insulin resistance. Mounting evidence suggests that insulin therapy not only produces symptomatic improvements, but also that insulin treatment can help correct the underlying pathogenetic mechanisms responsible for type 2 diabetes, namely, insulin resistance and impaired insulin secretion. In a number of
4.1. Disadvantages of existing insulin products Although insulin is the most effective therapy for reducing blood-glucose levels, the current injectable forms of insulin present several drawbacks [24]. The need for multiple injections daily is a substantial disadvantage. This is due to a number of factors including needle phobia, non-physiological delivery to the wrong target tissues, poor pharmacodynamics and often non-ideal treatment initiation. In regards to adverse effects, the risk of hypoglycemic episodes and weight gain represent concerns for injection therapy with insulin. Moreover, the safety of long-acting insulin analogs has recently been questioned. A number of recent studies suggest that these long-acting synthetic chemical entities may produce an increased risk of breast cancer. As reviewed by Smith and Gale [25] a number of retrospective studies submitted in 2008 and 2009 suggest that
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use of insulin glargine is, after adjustment for dose, associated with a possible increase in tumor risk in humans. Interpretation of this analysis proved controversial, but the implications are serious. In the case of glargin, the most commonly used long-acting insulin analog, the question has been raised as to whether this insulin analogue may have specific growth promoting potential, which could be expressed as tumor-promoting activity in patients [26]. 4.2. Issues in development of new chemical entities for treatment of diabetes By many accounts, the pharmaceutical industry is experiencing a severe decline in research productivity. More and more capital is being invested in research and development, but the rate at which new drugs are introduced to the market is failing to keep pace. According to the FDA, new compounds entering Phase I development today have only an 8% chance of reaching the market versus a 14% chance 15 years ago. And the Phase III failure rate has risen to 50% versus 20% just ten years ago [27]. This issue is particularly apparent in the field of diabetes. Moreover, in 2008, FDA introduced a new guideline for clinical development of anti-diabetes agents [28]. This new guideline stipulates a minimum number of test subjects to be enrolled and a minimum duration of the evaluation period on pivotal clinical trials. The reason for the high safety demands of novel anti-diabetes treatments involve (i) a rapidly increasing size of the target population, (ii) a decrease in the average age at diagnosis and (iii) the life-long requirement for therapy of subjects once obtaining the diagnosis. Furthermore, in 2008, concern over reports that link diabetes drugs to cardiac problems, U.S. drug regulators today ask diabetesdrug makers for more safety data. These requests for additional data could delay new product approvals by years and add millions of dollars to development and post-market commitment costs [29]. 4.3. The advantage of portal insulin delivery The basic goal of tight control of blood-glucose using intensive insulin therapy is to mimic insulin secretion by the normal pancreas. Today, this involves designing a regimen that includes a long-acting or intermediate-acting insulin preparations that approximates basal insulin secretion (i.e., the small amount of insulin the pancreas secretes continuously) and a short-acting insulin preparation that is administered before mealtimes and mimics the extra insulin the pancreas secretes to handle the postprandial rise in blood-glucose levels. The advent of insulin pumps is one more recent approach to fine-tuning delivery in order to gain greater control. There have been a number of pharmaceutical approaches to developing a non-invasive delivery route for insulin, most of them topical (e.g. patches) or inhalation. These share the same weakness as injectable insulin: the delivered protein passes first into the peripheral circulation and only thereafter, in much diluted form, into the liver. Thus topically and subcutaneously administered insulin result in fat and muscle being exposed to higher insulin levels than the liver. This is in contrast to endogeneous insulin which is delivered from the pancreas into the portal system and the liver. Oral delivery would share this advantage. The emergence of new non-invasive delivery technologies that allows administration of insulin through the portal vein instill hope for therapeutic breakthrough. For example, reports on portal delivery of insulin from islet grafts in the portal vein demonstrate that portal delivery of insulin is important in maintenance of normal whole-body insulin sensitivity [30,31]. Moreover, the advantages of portal insulin delivery are intensively discussed in the publications
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dedicated to development of oral insulin delivery systems [32]. Oral insulin administration better mimics endogeneous production and is more convenient for the patient than conventional subcutaneous insulin administration. Given orally and delivered to the portal vein normal vein/arterial insulin distribution would be restored. In addition, portal delivery of insulin may present advantages in terms of lower risk for carcinogenesis. Since insulin after absorption undergoes a substantial first pass clearance, only a small fraction of the administered drug will reach the extrahepatic circulation. After oral delivery, the absorbed insulin will predominantly exert its effect in the liver where it also is metabolized. Consequently, upon oral delivery of insulin, a lower continuous extrahepatic insulin tone is predicted to occur which may be advantageous in the light of insulin’s mitogenic properties. 4.4. Industry efforts in the field of oral insulin The various challenges associated with the production of a reliable insulin formulation for peroral delivery includes (i) maintaining storage stability of the active protein, (ii) avoiding enzymatic degradation in the gastrointestinal tract and (iii) overcoming poor spontaneous insulin permeability through the gastrointestinal system. Despite the multiple technical challenges several companies have announced initiatives in this direction, including Apollo Life Sciences, Biocon, Diabetology Ltd., Emisphere, Oramed and Orin Pharmaceuticals AG. One may speculate that the administration of human recombinant insulin without chemical modifications or co-formulation with any new chemical entity may provide advantages in terms of development risks. For example, three biotechnology companies—Diabetology Ltd., Oramed and Orin Pharmaceuticals have indicated progress in this respect and have in fact reached the stage of Phase II clinical trials of oral insulin preparations. Diabetology Ltd. has developed a delivery system which significantly increases the absorption of peptides, proteins and other macromolecules across the intestinal wall when delivered orally without any chemical modification of the active compounds. The delivery system is based on a simple mixture of components consisting of excipients with absorption-enhancing activities. Results were recently announced from 10-day repeat-dosing of CapsulinTM oral insulin in patients with T2D [33]. The study showed that CapsulinTM was able to improve glycemic control throughout the day, including mealtimes, with reduced glucose fluctuations and postprandial glucose rises. These observations were associated with significant improvements in HbA1C , weight and triglycerides between pre-study screen and study close. At the same time CapsulinTM was found to be safe and well tolerated with no serious adverse events and no hypoglycemia occurring. Another company, Oramed, has announced the completion of a Phase IIa stage clinical trial of ORMD 0801, which is a capsule formulation of insulin that incorporates adjuvants. These adjuvants are intended to protect the active protein while in transit through the harsh chemical environment of the gastrointestinal tract and promote its transport across the intestinal mucosa. ORMD 0801 was well tolerated by all patients and in two thirds of the subjects analyzed, statistically significant reductions in glucose as well as C-peptide were observed. Finally, Orin Pharmaceuticals AG is preparing a Phase II clinical trial in T2D for its oral insulin preparation. The company has developed a proprietary formulation consisting of dextran matrix for oral delivery of insulin. Being included in the dextran matrix, insulin is protected against proteolytic degradation in the gastric ventricle. Subsequently, the dextran matrix is degraded by endogenous enzymes in the mucosa of the small intestine resulting in targeted delivery at a site where insulin is spontaneously absorbed at an optimal rate. Early clinical testing in T2D patients has demonstrated absorption at clinically useful levels.
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Treatment of early stage T2D is going to require an unprecedented demonstration of safety for the patient. In the future, subjects will start treatment at earlier stages (and ages) perhaps without any other ailments. Moreover, subjects with T2D are likely to live longer and need to maintain the therapy for extended periods of time, perhaps for decades. Consequently, insulin, which is a naturally occurring hormone, will present advantages as compared to new chemical entities. In summary, a number of industry programs are currently evaluating non-invasive delivery approaches that more closely mimics the natural exposure and action of insulin as well as being more convenient and safe to the patient. 5. Concluding remarks Insulin is the most effective medicine at lowering hyperglycemia which can in turn decrease any level of elevated HbA1C to, or close to, the therapeutic goal. The effectiveness, cost, and, apart from hypoglycaemia, lack of severe side effects make insulin the ideal treatment for diabetes mellitus. New evidence point to a curative value of early insulin administration. Early introduction of insulin in pre-diabetics may in fact delay the onset of T2D. Non-invasive delivery approaches that more closely mimic the natural exposure route for the hormone would present substantial advantages over existing diabetes drugs. Several clinical studies are ongoing with the objective of assessing the therapeutic potential of oral delivery technologies for insulin. While the pharmaceutical industry has largely failed to develop new agents that can fundamentally improve the disease course of T2D, new delivery approaches of insulin that present insulin to the enterohepatic circulation offers promise to fundamentally change the pharmacological treatment of diabetes mellitus. Acknowledgement The authors would like to thank Dr. Anthony Wild for advice and comments on the manuscript. References [1] Meetoo D, McGovern P, Safadi R. An epidemiological overview of diabetes across the world. Br J Nurs 2007;16:1002–7. [2] Ray JA, Valentine WJ, Secnik K, Oglesby AK, Cordony A, Gordois A, et al. Review of the cost of diabetes complications in Australia, Canada, France, Germany, Italy and Spain. Curr Med Res Opin 2005;21:1617–29. [3] Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 2004;27:1047–53. [4] Mellbin LG, Malmberg K, Norhammar A, Wedel H, Rydén L, DIGAMI 2 Investigators. The impact of glucose lowering treatment on long-term prognosis in patients with type 2 diabetes and myocardial infarction: a report from the DIGAMI 2 trial. Eur Heart J 2008;29:166–76. [5] Calvert MJ, McManus RJ, Freemantle N. The management of people with type 2 diabetes with hypoglycaemic agents in primary care: retrospective cohort study. Fam Practice 2007;24:224–9. [6] Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of longterm complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977–86. [7] Niswender K. Early and aggressive initiation of insulin therapy for type 2 diabetes: what is the evidence? Clin Diabetes 2009;27:60–8. [8] Perry JR, Frayling TM. New gene variants alter type 2 diabetes risk predominantly through reduced beta-cell function. Curr Opin Clin Nutr Metab Care 2008;11:371–7.
[9] Wajchenberg BL. -Cell failure in diabetes and preservation by clinical treatment. Endocr Rev 2007;28:187–218. [10] Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. ß-Cell deficit and increased ß-cell apoptosis in humans with type 2 diabetes. Diabetes 2003;52:102–10. [11] Chen HS, Wu TE, Jap TS, Hsiao LC, Lee SH, Lin HD. Beneficial effects of insulin on glycemic control and beta-cell function in newly diagnosed type 2 diabetes with severe hyperglycemia after short-term intensive insulin therapy. Diabetes Care 2008;31:1927–32. [12] Ryan EA, Imes S, Wallace C. Short-term intensive insulin therapy in newly diagnosed type 2 diabetes. Diabetes Care 2004;27:1028–32. [13] Della Casa L, del Rio G, Glaser B, Cerasi E. Effect of 6-month gliclazide treatment on insulin release and sensitivity to endogenous insulin in NIDDM: role of initial continuous subcutaneous insulin infusion-induced normoglycemia. Am J Med 1991;90:37S–45S. [14] Ilkova H, Glaser B, Tunckale A, Bagriac¸ik N, Cerasi E. Induction of long-term glycemic control in newly diagnosed type 2 diabetic patients by transient intensive insulin treatment. Diabetes Care 1997;20:1353–6. [15] Kulkarni RN. Receptors for insulin and insulin-like growth factor-1 and insulin receptor substrate-1 mediate pathways that regulate islet function. Biochem Soc Trans 2002;30:317–22. [16] Beith JL, Alejandro EU, Johnson JD. Insulin stimulates primary beta-cell proliferation via Raf-1 kinase. Endocrinology 2008;149:2251–60. [17] Foley JE, Kashiwagi A, Verso MA, Reaven G, Andrews J. Improvement in in vitro insulin action after one month of insulin therapy in obese noninsulin-dependent diabetics. Measurements of glucose transport and metabolism, insulin binding, and lipolysis in isolated adipocytes. J Clin Invest 1983;72:1901–9. [18] Skyler JS. Insulin therapy in type II diabetes: who needs it, how much of it, and for how long? Postgrad Med 1997;101:85–96. [19] Fontbomme AM, Eschwege EM. Insulin and cardiovascular disease: Paris Prospective Study. Diabetes Care 1991;14:461–9. [20] UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837–53. [21] De Witt DE, Hirsch IB. Outpatient insulin therapy in type 1 and type 2 diabetes mellitus: a scientific review. JAMA 2003;289:2254–64; Dailey GE. Early insulin: an important therapeutic strategy. Diabetes Care 2005;28:220–1. [22] Peyrot M. Psychological insulin resistance: overcoming barriers to insulin therapy. Practical Diabetol 2004;23:6–12. [23] Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2009;32:193–203. [24] Peyrot M, Rubin RR, Lauritzen T, Skovlund SE, Snoek FJ, Matthews DR, et al. Resistance to insulin therapy among patients and providers: results of the cross-national Diabetes Attitudes, Wishes, and Needs (DAWN) study. Diabetes Care 2005;28:2673–9. [25] Smith U, Gale EAM. Does diabetes therapy influence the risk of cancer? Diabetologia 2009;52:1441–5. [26] Kurtzhals P, Schäffer L, Sørensen A, Kristensen C, Jonassen I, Schmid C, et al. Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. Diabetes 2000;49:999–1005. [27] Tempio JS. Squeeze play 2008: price pressure and declining R&D productivity. Pharmaceut Proc 2008;7:121–31. [28] Guidance for industry: diabetes mellitus: developing drugs and therapeutic biologics for treatment and prevention. Food and Drug Administration, Center for Drug Evaluation and Research (CDER). February 2008. [29] Guidance for industry: diabetes mellitus—evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. Food and Drug Administration, Center for Drug Evaluation and Research (CDER). December 2008. [30] Katsuragi I, Okeda T, Yoshimatsu H, Utsunomiya N, Ina K, Sakata T. Transplantation of normal islets into the portal vein of Otsuka Long Evans Tokushima Fatty Rats prevents diabetic progression. Exp Biol Med 2001;226: 681–5. [31] Guan J, Zucker PF, Behme MT, Zhong R, Atkison P, Dupre J. Insulin resistance prevented by portal delivery of insulin in rats with renal subcapsular islet grafts. Diabetes 1997;46:372–8. [32] Arbit E, Kidron M. Oral insulin: the rational for this approach and current developments. J Diabetes Sci Technol 2009;3:562–7. [33] Diabetology Ltd. corporate web site. Repeat dosing data for Capsulin phase II in type 2 diabetes presented at the EASD Conference in Rome, Sep 2008. http://www.diabetology.co.uk/EASD Rome Ph2 release 0908.htm.