Short-term intensied insulin treatment in type 2 diabetes: long-term effects on -cell function

R. Retnakaran1,2 & B. Zinman1,2,3

1 Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, Toronto, Canada 2 Division of Endocrinology, University of Toronto, Toronto, Canada 3 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada

The natural history of type 2 diabetes (T2DM) is characterized by progressive deterioration of pancreatic -cell function, leading to worsening glycemia over time. As current antidiabetic therapies have not yet been shown to profoundly alter this natural history, many patients ultimately will require exogenous insulin therapy to obtain adequate glycemic control. Interestingly, the temporary use of short-term intensive insulin therapy early in the course of T2DM has recently emerged as a therapeutic option that may offer favourable long-term effects on -cell function. Indeed, after receiving this treatment, many patients will experience sustained euglycemia without requiring any antidiabetic therapy. This apparent remission of diabetes is likely secondary to improved -cell function and can last for more than a year, although it is not sustained and hyperglycemia eventually will return. Nevertheless, owing to its effects on -cell function, short-term intensive insulin therapy holds promise as a means for modifying the natural history of T2DM and warrants further study in this context. In this report, we will review the rationale and evidence underlying this interesting therapeutic option, and its implications for both clinical research and the management of patients with T2DM. Keywords: clinical trials, intensive insulin therapy, -cell function
Date submitted 15 March 2012; date of nal acceptance 11 April 2012

Introduction
The natural history of type 2 diabetes (T2DM) is characterized by the progressive deterioration of pancreatic -cell function over time [1]. Indeed, as observed in the United Kingdom Prospective Diabetes Study (UKPDS), this decline in -cell function correlates with worsening glycemic control, leading to progressively increased requirements for glucose-lowering therapy [2,3]. Importantly, however, no current antidiabetic medication has yet been shown to profoundly modify the inexorable deterioration of -cell function in patients with T2DM [3,4]. As such, despite the typical addition of more and more glucose-lowering medication over time, many patients ultimately will require insulin therapy (i.e. when their functional -cell capacity declines to the point where glycemic control can no longer be achieved without exogenous insulin supplementation). Thus, in clinical practice, insulin therapy is typically introduced late in the course of disease and then continued indenitely thereafter. In the clinical management of T2DM, the preservation of -cell function remains an elusive goal, albeit one with great potential to favourably alter the natural course of this condition. Accordingly, with any new antidiabetic medication, a critical question to address is whether it could possibly
Correspondence to: Dr. Bernard Zinman CM, MD, Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, 60 Murray Street, Suite L5-024, Mailbox-17, Toronto, ON, Canada M5T3L9. E-mail: zinman@lunenfeld.ca

preserve -cell function. Interestingly, in this context, there has been growing recent interest in the potential application of the most fundamental antidiabetic therapy of all, namely insulin itself, for this purpose. Indeed, the use of short-term intensive insulin therapy early in the course of T2DM has emerged as a therapeutic option that may offer favourable long-term effects on -cell function [4]. Thus, in this report, we will review the rationale and evidence underlying this interesting concept, and its implications for both clinical research and the management of patients with T2DM.

-Cell Failure in T2DM

The progressive deterioration of insulin secretory function in T2DM is accompanied by a loss of -cell mass, though the temporal and causal associations between these two related processes (loss of function and loss of mass) remain to be fully elucidated [58]. On assessment at autopsy, patients with T2DM have been found to have a 60% reduction in -cell mass, as compared to non-diabetic controls [6]. Furthermore, pancreata from subjects with T2DM show evidence of increased -cell apoptosis and islet amyloid deposition [6]. At present, the precise pathologic mechanisms leading to -cell failure are not certain. However, factors that have been implicated as potentially contributing to this process include glucotoxicity, lipotoxicity, islet inammation and amyloid deposition [5]. While short-term intensive insulin therapy early in the course of T2DM could affect any of these factors, its effects

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on glucotoxicity and lipotoxicity may be of particular interest. Glucotoxicity refers to the deleterious (but potentially reversible) effects of chronic hyperglycemia on the secretion of insulin by the -cells. Indeed, rst-phase insulin secretion begins to exhibit abnormalities at blood glucose 5.6 mmol/l and is actually abolished at levels of just 6.4 mmol/l [9]. Lipotoxicity refers to the deleterious effects of excessive chronic exposure to free fatty acids (FFAs). Specically, in subjects who are predisposed to T2DM (as compared to the general population), persistently elevated FFAs may contribute to progressive -cell failure [5,10]. In this context, it is of interest to note that, through its glucose disposal and antilipolytic effects, insulin therapy could potentially reduce the exposure of the -cells to both excessive glycemia and FFAs. Theoretically, however, if these exposure-limiting effects are to improve -cell function, then the insulin therapy needs to be introduced at an early stage in the natural history of T2DM, when sufcient -cell mass remains to enable functional improvement with the alleviation of reversible glucotoxicity and lipotoxicity.

DIABETES, OBESITY AND METABOLISM

a clinical trial by Weng et al. in which 382 patients with recently diagnosed T2DM were randomized to 25 weeks treatment using CSII, MDI or oral antidiabetic medications (consisting of metformin, gliclazide, or, in most patients, both). These therapies were titrated to glycemic targets of fasting glucose <6.1 mmol/l and 2-h postprandial glucose <8.0 mmol/l after each of breakfast, lunch and dinner, with treatment maintained for 2 weeks after the targets were achieved. With this protocol, the glycemic targets were achieved in a mean 7.9 days in 92.1% of participants. Moreover, the rates of euglycemia at 1 year were 51.1 and 44.9% in those who had received CSII and MDI, respectively, signicantly higher than the 26.7% rate in the oral antidiabetic (OAD) group. Overall, the clinical studies shown in Table 1 have demonstrated that short-term intensive insulin therapy can exert long-lasting effects on glycemic control in patients with newly diagnosed T2DM.

Effect of Short-term Intensive Insulin Therapy on -cell Function

The long-term impact on glycemic control is likely due to the effects of this therapy on -cell function. Notably, a consistent nding in previous studies has been that temporary intensive insulin therapy can improve -cell function, particularly in those individuals that attain near-normoglycemic remission [11,12,14,15,1719]. In the trial by Weng et al. rst-phase insulin secretion [as assessed by the acute insulin response to glucose (AIRg ) on intravenous glucose tolerance test], which had been absent at baseline, was partially restored when assessed 2 days after the completion of intensive therapy (whether by CSII, MDI or oral medications) [14]. Other indices of -cell function similarly improved in all three treatment groups, including the Homeostasis Model of Assessment of -cell function (HOMA-B) and fasting proinsulin : insulin ratio. Most importantly, the improvement in -cell function was relevant to the persistence of euglycemia at 1 year. Indeed, in the CSII and MDI groups, the patients that maintained persistent remission did not experience a signicant decline in AIRg at 1 year from that which was attained 2 days after the intervention.

Short-term Intensive Insulin Therapy in T2DM

The strategy of implementing short-term intensive insulin therapy early in the course of T2DM has been evaluated in clinical studies (Table 1). In these studies, insulin has been administered by either continuous subcutaneous insulin infusion (CSII) or multiple daily injections (MDI) for typically 25 weeks [1117]. Most of the studies have been performed in subjects with newly diagnosed diabetes, in whom the goal of this treatment strategy was the achievement of glycemic remission wherein the patients are able to maintain normal glucose levels without any antidiabetic medication after cessation of the short course of insulin. As shown in Table 1, this remission of T2DM was indeed achieved in the vast majority of newly diagnosed patients. Furthermore, euglycemia persisted for 1 year in approximately 40% of the subjects from these studies (Table 1) and has continued for up to 2 years or longer in some cases [12,18]. Of particular note is the largest study to date [14],

Table 1. Studies using early short-term intensive insulin therapy (either CSII or MDI) to induce sustained euglycemia off therapy in patients with either (i) newly diagnosed T2DM or (ii) longer duration of T2DM.

Studies Newly diagnosed T2DM Li et al. [11] Ilkova et al. [12] Ryan et al. [13] Weng et al. [14]

n 138 13 16 382

Age (years) 49 50 52 51 51 54 56

Duration of T2DM New New New New New 7.2 years 5.9 years

Baseline A1c (%) 10.1 11.0 11.8 9.7 11.0 13.2 7.0

Insulin or OAD therapy CSII CSII MDI CSII MDI OAD CSII CSII MDI

Duration of therapy (days) 6.3 3.9 14 1421 1435 1435 1435 1421 53.6 39 28 56

Achieved euglycemia with therapy (%) 91.3 92.3 88.9 97.1 95.2 83.5 80.0 34.4 67.6

Maintained euglycemia at 1 year (%) 47.1 n/a 43.8 51.1 44.9 26.7 55.1 34 n/a

Chen et al. [15] 187 Longer duration of T2DM Park and Choi [16] 91 Retnakaran et al. [17] 34

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Table 2. Predictors of successful achievement of post-insulin sustained euglycemia at baseline, during short-term intensive insulin therapy, and immediately after therapy. Predictors At baseline Better glycemic control Higher late-phase insulin secretion Higher BMI Higher insulin resistance Shorter duration of T2DM Fewer chronic vascular complications Greater self-care adherence During insulin therapy Faster achievement of glycemic targets Smaller exogenous insulin requirement Immediately after insulin therapy Better glycemic control Greater improvement in -cell function References [14,16] [17] [14,16] [15] [16,18] [16] [15] [14,17] [13,17] [11,1315,18] [11,14,15,17]

Interestingly, in contrast, AIRg declined signicantly by 1 year in those who achieved remission in the OAD group. Taken together, these data suggest that the preservation of rst-phase insulin secretion likely contributed to the higher rates of remission achieved with the intensive insulin regimens. The mechanism by which intensive insulin therapy may improve -cell function remains unclear. It does appear, however, that the elimination of glucotoxicity may not be the sole basis for this improvement. Specically, in comparing short-term intensive treatment with CSII, MDI and OADs, the study by Weng et al. showed that all three regimens yielded high rates of initial euglycemia but that insulin therapy (by either CSII or MDI) was associated with signicantly higher rates of remission and preservation of rst-phase insulin secretion after 1 year [14]. Similarly, in a study in which 44 newly diagnosed patients with severe hyperglycemia (dened as fasting glucose >16.7 mmol/l or random glucose >22.2 mmol/l) received 1014 days of intensive insulin therapy followed by randomization to either (i) 6 months of insulin followed by 6 months of OADs or (ii) 12 months treatment with OADs, the insulin group achieved better glycemic control and -cell function at 1 year (even when restricted to only those with A1c < 7.0%) [20]. These apparent benecial effects of insulin, as compared to OADs, suggest that the relevant mechanisms underlying the long-term improvement in -cell function likely extend beyond glucose-lowering alone. Besides glucose-lowering, other properties of insulin that may contribute to improved -cell function include its antilipolytic, antiinammatory and antiapoptotic effects. In this regard, Li et al. sought to explore the protective role of insulin on -cell function using a rat model of diabetes induced by streptozotocin and high-fat feeding [21]. They found that insulin therapy improved -cell function, markedly reduced islet fat content, and increased -cell area through decreased apoptosis and increased -cell proliferation [21]. These data are suggestive of direct effects of insulin on -cell preservation, though the relevant mechanisms remain to be determined. Finally, the role of incretin physiology in this setting also warrants study. Specically, 4 weeks of near-normalization of blood glucose has been shown to improve the attenuated -cell responsiveness to both glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide in patients with T2DM, while not affecting the secretion of either of these hormones [22,23].

Predictors of the Response to Short-term Intensive Insulin Therapy

While clinical studies have consistently shown that shortterm intensive insulin therapy can improve -cell function and longer-term glycemic control, it is also clear that these effects are not permanent and that glucose levels inevitably eventually rise. Furthermore, there is heterogeneity in the patient response, as evident in the variable duration of euglycemia after treatment (Table 1). In this context, predictors of treatment success warrant closer examination, as they may provide insight on the underlying physiology that is relevant to individual response and hold implications for patient selection.

Predictors of a positive response to short-term intensive insulin therapy can be divided into three groups based on their timing: (i) baseline predictors, (ii) factors that emerge during treatment and (iii) those that are apparent immediately after treatment (Table 2). Upon consideration of their likely basis, it would appear that many of these factors that predict the successful achievement of sustained euglycemia are likely indicative of greater underlying residual -cell function (that presumably may then be improved by short-term insulin therapy). Specically, at baseline, better glycemic control, higher late-phase insulin secretion and shorter duration of diabetes may all reect greater residual -cell function [14,1618]. Similarly, higher BMI and insulin resistance may point to a relatively greater contribution of secretory stress (rather than -cell failure alone) leading to the development of T2DM in the setting of comparatively greater residual -cell function than that in which diabetes would otherwise arise [1416]. During therapy, the faster achievement of glycemic targets and lower requirements for exogenous insulin again may point to the recovery of greater underlying -cell function [13,14,17]. Indeed, after therapy, a greater improvement in -cell function from that which was observed at baseline has been a consistent predictor of the response to short-term insulin therapy in previous studies [11,14,15,17]. Taken together, these data suggest the following model. The -cell dysfunction observed early in the course of T2DM reects the combined effects of a component that is amenable to reversal with short-term insulin therapy (such as glucotoxicity) and an intrinsic component that may not be responsive to this therapy. Since existing indices of -cell function cannot distinguish between these two components, the baseline measurement of -cell function cannot predict response to therapy. For example, a patient whose -cell function reects a comparatively high burden of the reversible component coupled with relatively preserved underlying residual function may respond much more favourably to short-term intensive insulin therapy than another patient with similar overall baseline function but a lesser burden of reversible dysfunction

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Beta-cell Function in Patient A Reversible component of beta-cell dysfunction

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Beta-cell Function in Patient B

Reversible component of beta-cell dysfunction

Non-reversible component of beta-cell dysfunction

Non-reversible component of beta-cell dysfunction

Figure 1. Schematic showing how two patients with similar overall levels of -cell function can have different proportions of reversible and non-reversible dysfunction. Patient A has a greater reversible component and a smaller non-reversible component (indicative of greater underlying residual -cell function). As such, patient A may experience a greater recovery of -cell function in response to short-term intensive insulin therapy.

combined with greater loss of residual capacity (gure 1). This model would explain why baseline -cell function may not predict response to therapy whereas the change in -cell function immediately after short-term insulin therapy is a consistent predictor of sustained euglycemia. From the studies of short-term intensive insulin therapy to date, there are two observations in particular that support the importance of residual underlying -cell function. First, patients that respond positively (i.e. achieve sustained euglycemia) have required less exogenous insulin during intensive therapy than their peers, suggestive of a comparatively greater contribution of endogenous insulin secretion [13,17]. Secondly, a consistent nding across the studies has been that, when receiving intensive insulin therapy early in the course of T2DM, patients experience relatively little hypoglycemia despite targeting near-normal glycemic control [11,13,14,17]. This observation is in sharp contrast to the usual increased risk of hypoglycemia that arises as one approaches normoglycemia when administering insulin therapy late in the course of disease in clinical practice. As only the -cell can nely regulate insulin secretion to achieve normal glycemic control without hypoglycemia, these data may point to the recovery of residual -cell function in the response to insulin therapy in early T2DM.

Table 3. Potential benets of short-term intensive insulin therapy early in the course of T2DM.

Preservation of -cell function. Limit cumulative exposure to chronic hyperglycemia. Low risk of hypoglycemia when giving insulin therapy in the setting of preserved -cell function. Positive effects on patient quality of life.

and treatment satisfaction [24]. Furthermore, Chen et al. have reported that positive patient attitudes may also feed forward as a predictor of sustained euglycemia following shortterm insulin therapy [15]. These data support the patient acceptability of early short-term insulin therapy and, coupled with the other benets as shown in Table 3, emphasize the need for consideration of this strategy in the clinical management of T2DM.

A Novel Application of Short-term Intensive Insulin Therapy in Clinical Research

As shown in gure 1, in patients with T2DM, the assessment of -cell function by existing methodologies may not reect the true degree of underlying -cell capacity, owing to the variable effects of reversible factors (such as glucotoxicity). Indeed, it is often overlooked that clinical studies evaluating the effects of antidiabetic therapies on -cell function are typically confounded by this limitation [25]. Furthermore, when studied in a hyperglycemic patient, the glucose-lowering activity of an antidiabetic therapy may confound the assessment of its effects on -cell function (since improved function in that setting may reect the elimination of glucotoxicity, rather than -cell preservation). It thus follows that elimination of the confounding effect of hyperglycemia is needed for the objective assessment of the capacity of antidiabetic therapies to preserve -cell function in T2DM. In this context, we have proposed the initial induction of normoglycemia using short-term intensive insulin therapy as a strategy for the unbiased evaluation of the capacity of medications to preserve -cell function in clinical trials [25].

Clinical Application of Short-term Intensive Insulin Therapy in Early T2DM

Though insulin is typically introduced late in the course of T2DM in clinical practice, the data reviewed herein suggest that there may be benets from the early introduction of short-term intensive insulin therapy (Table 3). These benets potentially may include the preservation of -cell function, lesser cumulative exposure to chronic hyperglycemia, and low risk of hypoglycemia when using insulin in the setting of preserved residual -cell function. Interestingly, we have recently demonstrated that, contrary to common patient and provider perception, the early institution of short-term intensive insulin therapy in patients with T2DM lead to signicant improvements in patient-reported quality of life

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cumulative exposure to chronic hyperglycemia. While the optimal approach for its implementation in practice remains to be determined, this treatment warrants further study, particularly owing to the unique disease-modifying benets that it may offer. Furthermore, relevant to clinical trial design, prerandomization intensive insulin therapy offers a useful strategy for objectively evaluating the -cell protective capacity of diabetes interventions that warrants consideration in the design of future clinical studies.

Sitagliptin

Placebo

200

Beta-cell function (AUCcpep/gluc / HOMA-IR)

Insulin Therapy

Sitagliptin vs Placebo*

160 120 80 40 0 Screen Rand Wk 12 Wk 24 Wk 36 Wk 48

Acknowledgements
R. R. holds a Canadian Institutes of Health Research (CIHR) Clinical Research Initiative New Investigator Award, Canadian Diabetes Association (CDA) Clinician-Scientist incentive funding and an Ontario Ministry of Research and Innovation Early Researcher Award. B. Z. holds the Sam and Judy Pencer Family Chair in Diabetes Research at Mount Sinai Hospital and University of Toronto.

* p=0.61 for treatment effect (sitagliptin vs placebo) following randomization

Figure 2. Plot of median -cell function by group during both the prerandomization intensive insulin therapy phase and the subsequent randomized therapy phase (sitagliptin vs. placebo) in the -cell Evaluation and Sitagliptin Trial (BEST). Adapted with permission from Retnakaran et al. [25].

Conict of Interest
None to declare.

Specically, by using a short course of intensive insulin therapy to rst eliminate glucotoxicity and improve -cell function prior to randomization, one can create a level playing eld upon which to objectively evaluate the -cell protective effects of antidiabetic therapies in randomized controlled trials. Indeed, we introduced this study design in the recently reported -cell Evaluation and Sitagliptin Trial (BEST) [25]. BEST was a double-blind, placebo-controlled randomized clinical trial in which subjects with T2DM underwent a short course of prerandomization intensive insulin therapy, after which only those with venous fasting glucose in the non-diabetic range off any antidiabetic therapy (i.e. indicative of improved -cell function) were randomized to either sitagliptin or placebo on a background of metformin and followed for 1 year. The objective of this pilot study was to determine if sitagliptin could preserve -cell function, after its initial optimization with prerandomization insulin therapy. As shown in gure 2, intensive insulin therapy indeed improved -cell function prior to randomization, as anticipated. After stopping insulin therapy and randomizing participants to either sitagliptin or placebo, however, -cell function declined similarly in both the treatment and placebo control arms, suggesting that the enhanced -cell function achieved with prerandomization intensive insulin therapy could not be preserved with sitagliptin in this study population. This study conrmed our hypothesis that prerandomization short-term intensive insulin therapy can provide a strategy to enable the objective evaluation of the capacity of antidiabetic therapies to preserve -cell function in clinical trials.

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Conclusions
In the context of the natural history of T2DM, early introduction of short-term intensive insulin therapy appears to hold promise as a disease-modifying therapeutic option. Indeed, studies to date have shown that this therapy offers the capacity for long-term benecial effects on -cell function, thereby enabling sustained euglycemia and limiting

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13. Ryan EA, Imes S, Wallace C. Short-term intensive insulin therapy in newly diagnosed type 2 diabetes. Diabetes Care 2004; 27: 10281032. 14. Weng J, Li Y, Xu W et al. Effect of intensive insulin therapy on -cell function and glycaemic control in patients with newly diagnosed type 2 diabetes: a multicenter randomised parallel-group trial. Lancet 2008; 371: 17531760. 15. Chen A, Huang Z, Wan X et al. Attitudes toward diabetes affect maintenance of drug-free remission in patients with newly diagnosed type 2 diabetes after short-term continuous subcutaneous insulin infusion treatment. Diabetes Care 2012; 35: 474481. 16. Park S, Choi SB. Induction of long-term normoglycemia without medication in Korean type 2 diabetes patients after continuous subcutaneous insulin infusion therapy. Diabetes Metab Res Rev 2003; 19: 124130. 17. Retnakaran R, Yakubovich N, Qi Y, Opsteen C, Zinman B. The response to short-term intensive insulin therapy in type 2 diabetes. Diabetes Obes Metab 2010; 12: 6571. 18. Xu W, Li YB, Deng WP, Hao YT, Weng JP. Remission of hyperglycemia following intensive insulin therapy in newly diagnosed type 2 diabetic patients: a long-term follow-up study. Chin Med J 2009; 122: 25542559. 19. Hu Y, Li L, Xu Y et al. Short-term intensive therapy in newly diagnosed type 2 diabetes partially restores both insulin sensitivity and -cell function in subjects with long-term remission. Diabetes Care 2011; 34: 18481853.

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20. Chen HS, Wu TE, Jap TS, Hsiao LC, Lee SH, Lin HD. Benecial effects of insulin on glycemic control and -cell function in newly diagnosed type 2 diabetes with severe hyperglycemia after short-term intensive insulin therapy. Diabetes Care 2008; 31: 19271932. 21. Li HQ, Wang BP, Deng XL et al. Insulin improves -cell function in glucoseintolerant rat models induced by feeding a high-fat diet. Metabolism 2011; 60: 15661574. 22. Hjberg PV, Vilsbll T, Rabl R et al. Four weeks of near-normalisation of blood glucose improves the insulin response to glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes. Diabetologia 2009; 52: 199207. 23. Hjberg PV, Vilsbll T, Zander M et al. Four weeks of near-normalization of blood glucose has no effect on postprandial GLP-1 and GIP secretion, but augments pancreatic B-cell responsiveness to a meal in patients with type 2 diabetes. Diabet Med 2008; 25: 12681275. 24. Opsteen C, Qi Y, Zinman B, Retnakaran R. Effect of short-term intensive insulin therapy on quality of life in type 2 diabetes. J Eval Clin Pract 2012; 18: 256261. 25. Retnakaran R, Qi Y, Opsteen C, Vivero E, Zinman B. Initial short-term intensive insulin therapy as a strategy for evaluating the preservation of -cell function with oral anti-diabetic medications: a pilot study with sitagliptin. Diabetes Obes Metab 2010; 12: 909915.

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