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Early use of insulin in type 2 diabetes
Diabetes Research and Clinical Practice 68S1 (2005) S30–S35 www.elsevier.com/locate/diabres
Early use of insulin in type 2 diabetes Roy Eldor a,*, Erwin Stern b, Zvonko Milicevic c, Itamar Raz a a
Diabetes Research Center, Department of Medicine, Hadassah-Hebrew University Hospital, Jerusalem 91120, Israel b Beilinson Hospital, Petach Tikva, Israel c Eli Lilly Regional Medical Center, Vienna, Austria Available online 31 March 2005
Abstract Type 2 diabetes is a disease characterised by peripheral insulin resistance, as well as by pancreatic beta cell dysfunction. This process is in part due to elevated blood glucose and free fatty acids – termed glucolipotoxicity. The traditional pathway of treating type 2 diabetes in a stepwise manner, beginning with life style modifications and continuing with oral hypoglycaemic agents leads to a protracted period of unnecessary hyperglycaemia. A new approach, targeted at alleviating the deleterious effects of hyperglycaemia and elevated free fatty acids by acutely lowering both with intensive insulin therapy, has yielded prolonged remissions in therapy in which only diet was necessary to maintain normoglycaemia. This new approach, its rationale, benefits and misgivings are discussed in this review. # 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Early insulin treatment; Diabetes mellitus type 2; Glucotoxicity; Hypoglycemia
Insulin has been used since the 1920’s for the management of diabetes mellitus. It is a life-saving therapy for patients with type 1 diabetes and plays an important role in achieving glycaemia control and decreasing the risk of chronic complications in patients with type 2 diabetes (T2DM). Most patients with T2DM eventually require insulin therapy because of the progressive nature of their disease and subsequent pancreatic beta cell dysfunction [1]. Unlike type 1 diabetes there is uncertainty regarding the optimal position of insulin among a wide range of different treatment options such as increased physical activity, * Corresponding author. E-mail address: [email protected] (R. Eldor).
dietary intervention and oral hypoglycaemics [2]. No longer considered as a purely salvage treatment, insulin use is increasingly being considered earlier in the disease process. Still in many instances, the time to initiate insulin therapy can be a contentious decision. The traditional pathway for management of T2DM involves a stepwise approach, starting with lifestyle changes (with an emphasis on physical activity and dietary management) [3]. Failure to achieve normoglycaemia would lead to the commencement of an oral glucose lowering drug. Further on, and as shown in the United Kingdom Prospective Diabetes Study (UKPDS) blood glucose control continues to deteriorate, and in 2 years a second, and eventually a third oral hypoglycaemic agent would be needed [2]. To these one should
0168-8227/$ – see front matter # 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.diabres.2005.03.004
R. Eldor et al. / Diabetes Research and Clinical Practice 68S1 (2005) S30–S35
add other treatment modalities such as lipid-lowering agentsand antihypertensive drugs that are often required. Only when all else fails insulin would be added. When examined in a prospective, population-based study of over 7000 diabetic patients, this traditional stepwise approach revealed very low efficacy in maintaining normoglycaemia. By the time insulin therapy was begun, the average patient would accumulate 5 years with HbA1c of >8% and 10 years of HbA1c > 7% [4]. Early insulin use would therefore imply a more intensive approach to maintaining normoglycaemia, perhaps starting with insulin as the first drug to be administered after lifestyle changes, or when management with the first oral agent fails. Further on, combination regimens of insulin and oral hypoglycaemics, may have a synergistic effect in establishing adequate blood glucose control. The optimal strategy for insulin add-on therapy is yet to be determined. One approach would be the use of a basal long acting insulin (Glargine or bedtime NPH) [5] to supplement oral drug therapy relatively early in the natural history of T2DM [6]. An alternative approach is to use a rapidacting insulin analogue (Aspart-Lyspro) at mealtimes while leaving residual endogenous insulin secretion to maintain basal blood glucose control [7]. The choice of regimen might then depend on whether basal or post-prandial hyperglycaemia predominates.
1. The rationale and benefits of earlier insulin use The pathophysiology of T2DM involves a combination of peripheral insulin insensitivity (also known as insulin resistance) and progressive beta cell dysfunction leading to a temporal decline in insulin secretion. Both these processes begin before the onset of hyperglycaemia [8], which develops only when increasing peripheral insulin demands fail to be met by the ailing beta cell. Beta cell dysfunction is therefore a key pathophysiologic event in the development of diabetes. It is manifested in reduced conversion of proinsulin to insulin, altered patterns of insulin secretion and a quantitative defect in insulin secretion [9]. The subsequent development of hyperglycaemia further enhances these pathologic processes by beta cell glucotoxicity.
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Beta cell dysfunction as a result of glucotoxictiy is a combination of several pathologic processes. The initial stage of glucotoxicity involves beta cell exhaustion (a depletion of insulin stores), and beta cell desensitization, both of which are rapidly reversed upon return to normoglycaemia [10]. Further on, elevated blood glucose levels cause an increase in the production of reactive oxygen species, causing havoc in the unusually free radical prone beta cell [10,11]. This is usually accompanied by elevated levels of plasma free fatty acids (FFA), inflicting further deleterious effects on beta cells [12–14]. The mechanism of these effects is most probably similar to free radical mitochondrial damage in the beta cell (i.e. glucotoxicity) [15]. These effects can be reversed by powerful antioxidants in in vitro conditions and in laboratory animals [16]. Oxidative stress exerts its deleterious effect in a few distinct pathologic processes. In the mitochondria, oxidative stress causes an elevation of uncoupling protein 2 (UCP2) and a subsequent reduction in glucose stimulated insulin secretion [17]. Reactive oxygen species cause post-transcriptional defects in several key genes, among them the PDX gene, causing a reduction in insulin gene expression and production [10]. These effects lead to an elevated beta cell apoptosis [18,19] and islet amyloid polypeptide (IAPP) deposition [20,21] with a subsequent reduction of up to 60% in beta cell mass [19,22]. Further hyperglycaemia-induced beta cell apoptosis can be attributed to activation of the Fas pathway and autocrine release of interleukin 1 beta (IL-1beta) [23]. Glucotoxicity is at least partially reversible. When intensive insulin treatment (up to near normoglycaemia) was administered to patients, whose treatment by maximal doses of oral hypoglycaemics failed, a significant improvement in beta cell function occurred [24–26]. Furthermore, when administered early in the disease, intensive insulin therapy for short periods (even as short as 2 weeks at a time) induced a long ‘‘remission’’ (up to 13 months) during which diet alone was sufficient to maintain euglycaemia [27–29]. Comparative evidence between insulin therapy and oral agents based on the UKPDS, suggested that microvascular disease could be reduced either by insulin or oral agents. A reduction in HbA1c was also [2] achieved. Still insulin did seem to have an advantage since oral agents often have a limited
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R. Eldor et al. / Diabetes Research and Clinical Practice 68S1 (2005) S30–S35
glucose lowering efficacy in both short and long terms. Furthermore, insulin therapy may exert an additional protective effect on beta cell function. A trial comparing early insulin therapy to glibenclamide, done in Sweden, showed a significant reduction in HbA1c and in fasting plasma glucose as well as an elevation in glucagon-induced C-peptide excretion and plasma insulin levels after 2 years of insulin therapy, as compared with glibenclamide alone [30]. Thus, not only was diabetes better controlled in the insulin group, it is likely that beta cell function was better preserved. Other benefits of insulin therapy are its long and established safety profile, and its efficacy as monotherapy, thus avoiding polypharmacologic treatment that is inevitable with oral agents [31]. Exogenous insulin has been shown to restore normal insulin sensitivity [32]. Furthermore, insulin therapy in people with T2DM is associated with an improved lipid profile compared with some oral glucose lowering drugs [33], thus directly reducing lipotoxicity.
2. Side effects of early insulin therapy 2.1. Hypoglycaemia The potential risks associated with early use of insulin will be those qualitatively relevant to insulin therapy initiated at any stage in the natural history of diabetes. Hypoglycaemia is the most important of these. Symptomatic and biochemical hypoglycaemia is common in tightly controlled patients with T2DM, whether this is achieved with insulin or sulphonylureas [34]. In contrast, severe hypoglycaemia is rare and less abundant than in patients with type 1 diabetes receiving insulin therapy. Data from the Kumamoto study show a remarkable zero incidence of severe hypoglycaemia in people with type 2 diabetes receiving insulin therapy [35]. The risk of hypoglycaemia can be dependent on the treatment regimen or type of insulin. Yki-Jarvinen and colleagues [36] found differences between NPH insulin and insulin glargine, while Anderson et al. [37] reported differences when insulin lyspro or human insulin were used before meals. Relative infrequency and low risk of mortality [38], should not obscure its inherent dangers [39].
Hypoglycaemia may be compounded by ‘‘hypoglycaemia unawareness’’ especially in the elderly, and may be more severe and frequent in patients with renal impairment and decreased food intake [40,41]. Still hypoglycaemia is not exclusive to insulin therapy, and also a frequent complication of oral therapy, especially with sulphonylurea [42]. 2.2. Weight gain Weight gain in the region of 2.5–7.5 kg has been observed with insulin treatment during the first year [30,43]. Insulin causes weight gain through various mechanisms. It is known that it is an anabolic hormone causing muscle protein synthesis [44] and lipogenesis [45]. Insulin causes accumulation of sodium and subsequent water retention through a direct effect on sodium reabsorption in the renal distal tubule [46]. Treatment-associated weight gain in people with diabetes is also related to an improvement in blood glucose control with a decrease in energy loss via glucosuria [43]. Other factors such as increased dietary intake may also contribute particularly where increased carbohydrate is taken to prevent or treat hypoglycaemia [47]. Weight gain may be greater with more intensive insulin therapy, although short-acting or ultra long acting (glargine) insulin may be associated with less weight gain [48,49]. Some studies suggest that weight gain may be reduced by combining insulin with metformin [50]. Makimattila and colleagues [43] reported a mean weight gain of 7.5 kg after 1-year treatment with insulin alone compared with gain of only 3.8 kg with a combination of insulin and metformin. Furthermore, patients using this combination may have a reduced requirement for insulin and reduced dietary intake compared with those on insulin therapy alone. As noted above, in spite of causing hyperinsulinaemia and weight gain, the UKPDS demonstrated that long-term treatment with either insulin or sulphonylureas does not have any adverse impact on cardiovascular outcome [2]. Although some oral glucose lowering drugs, notably metformin, do not have these properties, the available evidence suggests that weight gain should not be a discouraging factor for those needing insulin early or earlier in the management of T2DM. In fact, in some situations
R. Eldor et al. / Diabetes Research and Clinical Practice 68S1 (2005) S30–S35
insulin could be considered earlier, irrespective of the potential for weight gain, such as among certain population groups, e.g. Hong Kong Chinese [51], where T2DM may have an earlier onset and be associated with a lower BMI and greater insulin deficiency. Other barriers to early use of insulin: people’s perception of needles is a significant barrier to insulin use [52]. However, uninformed perceptions, often based on larger needles designed for intravenous access need to be distinguished from needle phobia, which in rare cases can lead to severe avoidance behaviour with respect to both insulin injection and self-testing [53]. Other potential barriers such as cultural and logistical factors, the impact that insulin might have on a person’s employment, economic considerations and the ability of the patient or his caregiver to apply the injection schedule may limit its use.
3. Conclusions Treatment of T2DM can no longer solely focus on lowering blood glucose or treating insulin resistance. Reversal of beta cell dysfunction is becoming a major goal of therapy. Based on the evidence presented it would seem appropriate to consider at least a short course of insulin therapy in all patients who fail to normalise blood glucose after an initial management trial, especially in those who are markedly hyperglycaemic. Some patient populations benefit even more from early insulin therapy. Diabetic patients, in whom oral glucose lowering drugs are contraindicated or not tolerated sulphonylurea sensitivity, renal or liver impairment (metformin), and cardiac failure (thiazoldinediones), patients who have suffered a recent myocardial infarction [54] or women with gestational diabetes. New therapeutic strategies that deal with preserving beta cell function and mass in T2DM can focus on beta cell failure and apoptosis as a result of glucotoxictiy as their major treatment goals. Insulin has long been know to be an effective treatment for both, though emerging evidence exists for further benefit with drugs that have a specific anti-apoptotic effect. Of these, the best known is rosiglitazone shown to preserve beta cell function and first phase insulin secretion even better than insulin (independent of its
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hypoglycaemic effect) [55]. This effect appears to be achieved through a combination of reducing beta cell FFA content, an intrinsic antioxidant effect and a direct anti-apoptotic effect. Another emerging treatment option is the use of incretin hormones, among them glucagon like peptide1-GLP1, known to protect beta cells from glucose induced apoptosis [56]. Future treatment of T2DM should be based on an aggressive early glucose lowering regimen with beta cell preservation kept in mind. New and existing agents that can do both should be rewarded a higher place in the treatment plan. To date, insulin stands alone as the only therapeutic agent that has proved safe and at the same time highly efficacious in simultaneously achieving all these goals. References [1] R.A. De Fronzo, Pharmacologic therapy for type 2 diabetes mellitus, Ann. Intern. Med. 131 (1999) 281–303. [2] UK Prospective Diabetes Study Group, Intensive blood glucose control with sulfonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33), Lancet 352 (1998) 834–853. [3] J.M. Cheolade, A.D. Mooraolian, A rational approach to drug therapy of type 2 diabetes mellitus, Drugs 60 (2000) 95–113. [4] J.B. Brown, G.A. Nichols, A. Perry, The burden of treatment failure in type 2 diabetes, Diab. Care 27 (2004) 1535–1540. [5] D.M. Nathan, Insulin treatment of type 2 diabetes: the real deal, Endocrinol. Rounds 1 (1) (2002) 1–8. http://www.endocrinologyrounds.org. [6] M. Yki-Jarvinen, L. Ryysy, K. Nikkilu, Comparison of bedtime insulin regimens in patients with type 2 diabetes mellitus. A randomized controlled trial, Ann. Intern. Med. 130 (1988) 389–396. [7] E.J. Bastyr III, C.A. Stuart, R.G. Brodous, Therapy focused lowering postprandial glucose, not fasting glucose, may be superior for lowering HbA1c–10E2 Study Group, Diab. Care 23 (2000) 1236–1241. [8] E. Ferrannini, A. Gastaldelli, Y. Miyazaki, M. Matsuda, A. Mari, R.A. Defronzo, Beta-cell function in subjects spanning the range from normal glucose tolerance to overt diabetes: a new analysis, J. Clin. Endocrinol. Metab. (2004). [9] T.A. Buchanan, Pancreatic beta-cell loss and preservation in type 2 diabetes, Clin. Ther. 25 (Suppl. B) (2003) 32–46. [10] R.P. Robertson, J. Harmon, P.O. Tran, Y. Tanaka, H. Takahashi, Glucose toxicity in beta-cells: type 2 diabetes, good radicals gone bad, and the glutathione connection, Diabetes 52 (2003) 581–587. [11] K. Grankvist, S.L. Marklund, I.B. Taljedal, CuZn-superoxide dismutase, Mn-superoxide dismutase, catalase and glutathione peroxidase in pancreatic islets and other tissues in the mouse, Biochem. J. 199 (1981) 393–398.
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[12] M. Shimabukuro, Y.T. Zhou, M. Levi, R.H. Unger, Fatty acidinduced cell apoptosis: a link between obesity and diabetes, PNAS 95 (1998) 2498–2502. [13] Y. Lee, H. Hirose, Y.T. Zhou, V. Esser, J.D. McGarry, R.H Unger, Increased lipogenic capacity of the islets of obese rats: a role in the pathogenesis of NIDDM, Diabetes 46 (1997) 408– 413. [14] R. Lupi, F. Dotta, L. Marselli, S. Del Guerra, et al. Prolonged exposure to free fatty acids has cytostatic and pro-apoptotic effects on human pancreatic islets: evidence that beta-cell death is caspase mediated, partially dependent on ceramide pathway, and Bcl-2 regulated, Diabetes 51 (2002) 1437– 1442. [15] P. Schrauwen, M.K. Hesselink, Oxidative capacity, lipotoxicity, and mitochondrial damage in type 2 diabetes, Diabetes 53 (2004) 1412–1417. [16] R.P. Robertson, J. Harmon, P.O. Tran, V. Poitout, Beta cell glucose toxicity, lipotoxicity, and chronic oxidative stress in type 2 diabetes, Diabetes 53 (Suppl. 1) (2004) S119–S124. [17] S. Krauss, C.Y. Zhang, L. Scorrano, L.T. Dalgaard, et al. Superoxide-mediated activation of uncoupling protein 2 causes pancreatic beta cell dysfunction, J. Clin. Invest. 112 (2003) 1831–1842. [18] M.Y. Donath, D.J. Gross, E. Cerasi, N. Kaiser, Hyperglycemiainduced beta-cell apoptosis in pancreatic islets of Psammomys obesus during development of diabetes, Diabetes 48 (1999) 738–744. [19] A.E. Butler, J. Janson, S. Bonner-Weir, R. Ritzel, R.A. Rizza, P.C. Butler, Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes, Diabetes 52 (2003) 102–110. [20] A. Lorenzo, B. Razzaboni, G.C. Weir, B.A. Yankner, Pancreatic islet cell toxicity of amylin associated with type 2 diabetes mellitus, Nature 368 (1994) 756–760. [21] J. Janson, R.H. Ashley, D. Harrison, S. McIntyre, P.C. Butler, The mechanism of islet amyloid polypeptide toxicity is membrane disruption by intermediatesized toxic amyloid particles, Diabetes 48 (1999) 491–498. [22] M. Biarne´ s, M. Montolio, V. Nacher, M. Raurell, et al. Betacell death and mass in syngeneically transplanted islets exposed to short- and long-term hyperglycemia, Diabetes 51 (2002) 66–72. [23] K. Maedler, Donath MY, Beta-cells in type 2 diabetes: a loss of function and mass, Horm. Res. 62 (Suppl. 3) (2004) 67–73. [24] B. Glaser, G. Leibovich, R. Nesher, et al. Improved beta-cell function after intensive insulin treatment in severe non-insulindependent diabetes, Acta Endocrinol. 118 (1988) 365–373. [25] W.J. Andrews, B. Vasquez, M. Nagulesparan, et al. Insulin therapy in obese, non-insulin-dependent diabetes induces improvements in insulin action and secretion that are maintained for two weeks after insulin withdrawal, Diabetes 33 (1984) 634–642. [26] W.T. Garvey, J.M. Olefsky, J. Griffin, R.F. Hamman, O.G. Kolterman, The effect of insulin treatment on insulin secretion and insulin action in type II diabetes mellitus, Diabetes 34 (1985) 222–234. [27] H. Ilkova, B. Glaser, A. Tunckale, et al. Induction of long-term glycemic control in newly diagnosed type 2 diabetic patients
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R. Eldor et al. / Diabetes Research and Clinical Practice 68S1 (2005) S30–S35 [43] S. Makimattila, K. Nikkila, M. Yki-Jarvinen, Cause of weight gain during insulin therapy with and without metformin in patients with type 2 diabetes mellitus, Diabetologia 42 (1999) 406–412. [44] R.R. Wolfe, Effects of insulin on muscle tissue, Curr. Opin. Clin. Nutr. Metab. Care 3 (2000) 67–71. [45] S. Kersten, Mechanisms of nutritional and hormonal regulation of lipogenesis, EMBO Rep. 2 (2001) 282–286. [46] R.A. DeFronzo, The effect of insulin on renal sodium metabolism. A review with clinical implications, Diabetologia 21 (1981) 165–171. [47] S. Heller, Weight gain during insulin therapy in patients with type 2 diabetes mellitus, Diab. Res. Clin. Pract. 65 (Suppl. 1) (2004) 23–27. [48] DCCT (Diabetes Control and Complications Trial), Influence of intensive diabetes treatment on body weight and composition of adults with type 1 diabetes in the Diabetes Control and Complications Trial, Diab. Care 24 (2001) 1711–1721. [49] S.K. Garg, J.M. Paul, J.I. Karsten, L. Menditto, P.A. Gottlieb, Reduced severe hypoglycemia with insulin glargine in intensively treated adults with type 1 diabetes, Diab. Technol. Ther. 6 (2004) 589–595. [50] H. Yki-Jarvinen, L. Ryysy, K. Nikkila, et al. Comparison of bedtime insulin regimens in patients with Type 2 diabetes
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Early use of insulin in type 2 diabetes Roy Eldor a,*, Erwin Stern b, Zvonko Milicevic c, Itamar Raz a a
Diabetes Research Center, Department of Medicine, Hadassah-Hebrew University Hospital, Jerusalem 91120, Israel b Beilinson Hospital, Petach Tikva, Israel c Eli Lilly Regional Medical Center, Vienna, Austria Available online 31 March 2005
Abstract Type 2 diabetes is a disease characterised by peripheral insulin resistance, as well as by pancreatic beta cell dysfunction. This process is in part due to elevated blood glucose and free fatty acids – termed glucolipotoxicity. The traditional pathway of treating type 2 diabetes in a stepwise manner, beginning with life style modifications and continuing with oral hypoglycaemic agents leads to a protracted period of unnecessary hyperglycaemia. A new approach, targeted at alleviating the deleterious effects of hyperglycaemia and elevated free fatty acids by acutely lowering both with intensive insulin therapy, has yielded prolonged remissions in therapy in which only diet was necessary to maintain normoglycaemia. This new approach, its rationale, benefits and misgivings are discussed in this review. # 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Early insulin treatment; Diabetes mellitus type 2; Glucotoxicity; Hypoglycemia
Insulin has been used since the 1920’s for the management of diabetes mellitus. It is a life-saving therapy for patients with type 1 diabetes and plays an important role in achieving glycaemia control and decreasing the risk of chronic complications in patients with type 2 diabetes (T2DM). Most patients with T2DM eventually require insulin therapy because of the progressive nature of their disease and subsequent pancreatic beta cell dysfunction [1]. Unlike type 1 diabetes there is uncertainty regarding the optimal position of insulin among a wide range of different treatment options such as increased physical activity, * Corresponding author. E-mail address: [email protected] (R. Eldor).
dietary intervention and oral hypoglycaemics [2]. No longer considered as a purely salvage treatment, insulin use is increasingly being considered earlier in the disease process. Still in many instances, the time to initiate insulin therapy can be a contentious decision. The traditional pathway for management of T2DM involves a stepwise approach, starting with lifestyle changes (with an emphasis on physical activity and dietary management) [3]. Failure to achieve normoglycaemia would lead to the commencement of an oral glucose lowering drug. Further on, and as shown in the United Kingdom Prospective Diabetes Study (UKPDS) blood glucose control continues to deteriorate, and in 2 years a second, and eventually a third oral hypoglycaemic agent would be needed [2]. To these one should
0168-8227/$ – see front matter # 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.diabres.2005.03.004
R. Eldor et al. / Diabetes Research and Clinical Practice 68S1 (2005) S30–S35
add other treatment modalities such as lipid-lowering agentsand antihypertensive drugs that are often required. Only when all else fails insulin would be added. When examined in a prospective, population-based study of over 7000 diabetic patients, this traditional stepwise approach revealed very low efficacy in maintaining normoglycaemia. By the time insulin therapy was begun, the average patient would accumulate 5 years with HbA1c of >8% and 10 years of HbA1c > 7% [4]. Early insulin use would therefore imply a more intensive approach to maintaining normoglycaemia, perhaps starting with insulin as the first drug to be administered after lifestyle changes, or when management with the first oral agent fails. Further on, combination regimens of insulin and oral hypoglycaemics, may have a synergistic effect in establishing adequate blood glucose control. The optimal strategy for insulin add-on therapy is yet to be determined. One approach would be the use of a basal long acting insulin (Glargine or bedtime NPH) [5] to supplement oral drug therapy relatively early in the natural history of T2DM [6]. An alternative approach is to use a rapidacting insulin analogue (Aspart-Lyspro) at mealtimes while leaving residual endogenous insulin secretion to maintain basal blood glucose control [7]. The choice of regimen might then depend on whether basal or post-prandial hyperglycaemia predominates.
1. The rationale and benefits of earlier insulin use The pathophysiology of T2DM involves a combination of peripheral insulin insensitivity (also known as insulin resistance) and progressive beta cell dysfunction leading to a temporal decline in insulin secretion. Both these processes begin before the onset of hyperglycaemia [8], which develops only when increasing peripheral insulin demands fail to be met by the ailing beta cell. Beta cell dysfunction is therefore a key pathophysiologic event in the development of diabetes. It is manifested in reduced conversion of proinsulin to insulin, altered patterns of insulin secretion and a quantitative defect in insulin secretion [9]. The subsequent development of hyperglycaemia further enhances these pathologic processes by beta cell glucotoxicity.
S31
Beta cell dysfunction as a result of glucotoxictiy is a combination of several pathologic processes. The initial stage of glucotoxicity involves beta cell exhaustion (a depletion of insulin stores), and beta cell desensitization, both of which are rapidly reversed upon return to normoglycaemia [10]. Further on, elevated blood glucose levels cause an increase in the production of reactive oxygen species, causing havoc in the unusually free radical prone beta cell [10,11]. This is usually accompanied by elevated levels of plasma free fatty acids (FFA), inflicting further deleterious effects on beta cells [12–14]. The mechanism of these effects is most probably similar to free radical mitochondrial damage in the beta cell (i.e. glucotoxicity) [15]. These effects can be reversed by powerful antioxidants in in vitro conditions and in laboratory animals [16]. Oxidative stress exerts its deleterious effect in a few distinct pathologic processes. In the mitochondria, oxidative stress causes an elevation of uncoupling protein 2 (UCP2) and a subsequent reduction in glucose stimulated insulin secretion [17]. Reactive oxygen species cause post-transcriptional defects in several key genes, among them the PDX gene, causing a reduction in insulin gene expression and production [10]. These effects lead to an elevated beta cell apoptosis [18,19] and islet amyloid polypeptide (IAPP) deposition [20,21] with a subsequent reduction of up to 60% in beta cell mass [19,22]. Further hyperglycaemia-induced beta cell apoptosis can be attributed to activation of the Fas pathway and autocrine release of interleukin 1 beta (IL-1beta) [23]. Glucotoxicity is at least partially reversible. When intensive insulin treatment (up to near normoglycaemia) was administered to patients, whose treatment by maximal doses of oral hypoglycaemics failed, a significant improvement in beta cell function occurred [24–26]. Furthermore, when administered early in the disease, intensive insulin therapy for short periods (even as short as 2 weeks at a time) induced a long ‘‘remission’’ (up to 13 months) during which diet alone was sufficient to maintain euglycaemia [27–29]. Comparative evidence between insulin therapy and oral agents based on the UKPDS, suggested that microvascular disease could be reduced either by insulin or oral agents. A reduction in HbA1c was also [2] achieved. Still insulin did seem to have an advantage since oral agents often have a limited
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glucose lowering efficacy in both short and long terms. Furthermore, insulin therapy may exert an additional protective effect on beta cell function. A trial comparing early insulin therapy to glibenclamide, done in Sweden, showed a significant reduction in HbA1c and in fasting plasma glucose as well as an elevation in glucagon-induced C-peptide excretion and plasma insulin levels after 2 years of insulin therapy, as compared with glibenclamide alone [30]. Thus, not only was diabetes better controlled in the insulin group, it is likely that beta cell function was better preserved. Other benefits of insulin therapy are its long and established safety profile, and its efficacy as monotherapy, thus avoiding polypharmacologic treatment that is inevitable with oral agents [31]. Exogenous insulin has been shown to restore normal insulin sensitivity [32]. Furthermore, insulin therapy in people with T2DM is associated with an improved lipid profile compared with some oral glucose lowering drugs [33], thus directly reducing lipotoxicity.
2. Side effects of early insulin therapy 2.1. Hypoglycaemia The potential risks associated with early use of insulin will be those qualitatively relevant to insulin therapy initiated at any stage in the natural history of diabetes. Hypoglycaemia is the most important of these. Symptomatic and biochemical hypoglycaemia is common in tightly controlled patients with T2DM, whether this is achieved with insulin or sulphonylureas [34]. In contrast, severe hypoglycaemia is rare and less abundant than in patients with type 1 diabetes receiving insulin therapy. Data from the Kumamoto study show a remarkable zero incidence of severe hypoglycaemia in people with type 2 diabetes receiving insulin therapy [35]. The risk of hypoglycaemia can be dependent on the treatment regimen or type of insulin. Yki-Jarvinen and colleagues [36] found differences between NPH insulin and insulin glargine, while Anderson et al. [37] reported differences when insulin lyspro or human insulin were used before meals. Relative infrequency and low risk of mortality [38], should not obscure its inherent dangers [39].
Hypoglycaemia may be compounded by ‘‘hypoglycaemia unawareness’’ especially in the elderly, and may be more severe and frequent in patients with renal impairment and decreased food intake [40,41]. Still hypoglycaemia is not exclusive to insulin therapy, and also a frequent complication of oral therapy, especially with sulphonylurea [42]. 2.2. Weight gain Weight gain in the region of 2.5–7.5 kg has been observed with insulin treatment during the first year [30,43]. Insulin causes weight gain through various mechanisms. It is known that it is an anabolic hormone causing muscle protein synthesis [44] and lipogenesis [45]. Insulin causes accumulation of sodium and subsequent water retention through a direct effect on sodium reabsorption in the renal distal tubule [46]. Treatment-associated weight gain in people with diabetes is also related to an improvement in blood glucose control with a decrease in energy loss via glucosuria [43]. Other factors such as increased dietary intake may also contribute particularly where increased carbohydrate is taken to prevent or treat hypoglycaemia [47]. Weight gain may be greater with more intensive insulin therapy, although short-acting or ultra long acting (glargine) insulin may be associated with less weight gain [48,49]. Some studies suggest that weight gain may be reduced by combining insulin with metformin [50]. Makimattila and colleagues [43] reported a mean weight gain of 7.5 kg after 1-year treatment with insulin alone compared with gain of only 3.8 kg with a combination of insulin and metformin. Furthermore, patients using this combination may have a reduced requirement for insulin and reduced dietary intake compared with those on insulin therapy alone. As noted above, in spite of causing hyperinsulinaemia and weight gain, the UKPDS demonstrated that long-term treatment with either insulin or sulphonylureas does not have any adverse impact on cardiovascular outcome [2]. Although some oral glucose lowering drugs, notably metformin, do not have these properties, the available evidence suggests that weight gain should not be a discouraging factor for those needing insulin early or earlier in the management of T2DM. In fact, in some situations
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insulin could be considered earlier, irrespective of the potential for weight gain, such as among certain population groups, e.g. Hong Kong Chinese [51], where T2DM may have an earlier onset and be associated with a lower BMI and greater insulin deficiency. Other barriers to early use of insulin: people’s perception of needles is a significant barrier to insulin use [52]. However, uninformed perceptions, often based on larger needles designed for intravenous access need to be distinguished from needle phobia, which in rare cases can lead to severe avoidance behaviour with respect to both insulin injection and self-testing [53]. Other potential barriers such as cultural and logistical factors, the impact that insulin might have on a person’s employment, economic considerations and the ability of the patient or his caregiver to apply the injection schedule may limit its use.
3. Conclusions Treatment of T2DM can no longer solely focus on lowering blood glucose or treating insulin resistance. Reversal of beta cell dysfunction is becoming a major goal of therapy. Based on the evidence presented it would seem appropriate to consider at least a short course of insulin therapy in all patients who fail to normalise blood glucose after an initial management trial, especially in those who are markedly hyperglycaemic. Some patient populations benefit even more from early insulin therapy. Diabetic patients, in whom oral glucose lowering drugs are contraindicated or not tolerated sulphonylurea sensitivity, renal or liver impairment (metformin), and cardiac failure (thiazoldinediones), patients who have suffered a recent myocardial infarction [54] or women with gestational diabetes. New therapeutic strategies that deal with preserving beta cell function and mass in T2DM can focus on beta cell failure and apoptosis as a result of glucotoxictiy as their major treatment goals. Insulin has long been know to be an effective treatment for both, though emerging evidence exists for further benefit with drugs that have a specific anti-apoptotic effect. Of these, the best known is rosiglitazone shown to preserve beta cell function and first phase insulin secretion even better than insulin (independent of its
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hypoglycaemic effect) [55]. This effect appears to be achieved through a combination of reducing beta cell FFA content, an intrinsic antioxidant effect and a direct anti-apoptotic effect. Another emerging treatment option is the use of incretin hormones, among them glucagon like peptide1-GLP1, known to protect beta cells from glucose induced apoptosis [56]. Future treatment of T2DM should be based on an aggressive early glucose lowering regimen with beta cell preservation kept in mind. New and existing agents that can do both should be rewarded a higher place in the treatment plan. To date, insulin stands alone as the only therapeutic agent that has proved safe and at the same time highly efficacious in simultaneously achieving all these goals. References [1] R.A. De Fronzo, Pharmacologic therapy for type 2 diabetes mellitus, Ann. Intern. Med. 131 (1999) 281–303. [2] UK Prospective Diabetes Study Group, Intensive blood glucose control with sulfonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33), Lancet 352 (1998) 834–853. [3] J.M. Cheolade, A.D. Mooraolian, A rational approach to drug therapy of type 2 diabetes mellitus, Drugs 60 (2000) 95–113. [4] J.B. Brown, G.A. Nichols, A. Perry, The burden of treatment failure in type 2 diabetes, Diab. Care 27 (2004) 1535–1540. [5] D.M. Nathan, Insulin treatment of type 2 diabetes: the real deal, Endocrinol. Rounds 1 (1) (2002) 1–8. http://www.endocrinologyrounds.org. [6] M. Yki-Jarvinen, L. Ryysy, K. Nikkilu, Comparison of bedtime insulin regimens in patients with type 2 diabetes mellitus. A randomized controlled trial, Ann. Intern. Med. 130 (1988) 389–396. [7] E.J. Bastyr III, C.A. Stuart, R.G. Brodous, Therapy focused lowering postprandial glucose, not fasting glucose, may be superior for lowering HbA1c–10E2 Study Group, Diab. Care 23 (2000) 1236–1241. [8] E. Ferrannini, A. Gastaldelli, Y. Miyazaki, M. Matsuda, A. Mari, R.A. Defronzo, Beta-cell function in subjects spanning the range from normal glucose tolerance to overt diabetes: a new analysis, J. Clin. Endocrinol. Metab. (2004). [9] T.A. Buchanan, Pancreatic beta-cell loss and preservation in type 2 diabetes, Clin. Ther. 25 (Suppl. B) (2003) 32–46. [10] R.P. Robertson, J. Harmon, P.O. Tran, Y. Tanaka, H. Takahashi, Glucose toxicity in beta-cells: type 2 diabetes, good radicals gone bad, and the glutathione connection, Diabetes 52 (2003) 581–587. [11] K. Grankvist, S.L. Marklund, I.B. Taljedal, CuZn-superoxide dismutase, Mn-superoxide dismutase, catalase and glutathione peroxidase in pancreatic islets and other tissues in the mouse, Biochem. J. 199 (1981) 393–398.
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