Mark (not his real name) and his doctor then went on to discuss what he could do to manage his diabetes and prevent its complications: attend diabetes education, incorporate healthy lifestyle practices and start on oral antihyperglycemic medication. Mark’s outlook on life was very proactive and he decided that he wanted to take control of his diabetes instead of letting his new condition take control of him. He enrolled in a clinical trial called: The Action to Control Cardiovascular Risks in Diabetes Study (ACCORD).
In those days, we did not talk about stopping or delaying the natural progression of diabetes but the focus was on maintaining good glycemic control in order to prevent long-term vascular complications of diabetes. However, it is now recognized that the fundamental problem with current therapies for T2DM is the inability to prevent the ongoing deterioration of the pancreatic beta-cells that make insulin. If Mark were diagnosed with T2DM today, he may very well have asked another question: “Can we halt the progression of this condition?”
The UK Prospective Diabetes Study (UKPDS) showed that, at the time of diagnosis of diabetes, patients have already lost more than 50% of their ß-cell function. Furthermore, this ongoing loss of ß-cell function continues despite the use of antihyperglycemic agents, eventually leading to the need for permanent insulin therapy. Indeed, the deterioration of ß-cell function starts many years before the development of hyperglycemia (1- 4).
During the early stages of the disease process, individuals who are predisposed to T2DM are able to compensate for insulin resistance by increasing insulin production (hyperinsulinemia) in order to maintain their glucose levels within the normal range. Over time, however, the ß-cells are no longer able to compensate appropriately resulting in overt hyperglycemia and the subsequent diagnosis of T2DM.
Thus, the underlying problem in T2DM is progressive ß-cell dysfunction that worsens over time, resulting in the loss of glycemic control and an increased need for antihyperglycemic therapy. The ß-cell defect that drives this process is present well before the onset of hyperglycemia and is present in subjects that are at high risk of developing T2DM, even when these subjects have normal glucose tolerance (4,5).
So, why does ß-cell function decline in patients with diabetes and how can we stop this process?
The progressive decline of insulin secretory function in T2DM is accompanied by a loss of ß-cell mass presumably due to irreversible death of ß-cells. Factors contributing to pancreatic ß-cell dysfunction include:
- oxidative stress
- dysregulation of adipokines/cytokines
- amyloid deposition
- lipotoxicity (6)
While many of these factors lead to presumably irreversible death of ß-cells, Retnakaran (7) has noted that glucotoxicity and lipotoxicity are reversible early in the course of T2DM (8, 9). The impact of glucotoxicity is observed in the fact that the first phase of the normal biphasic secretion of insulin by the ß-cell is completely lost at a plasma glucose concentration of 6.4 mmol/L. Even at plasma glucose concentration of 5.6 mmol/L, there can be impairment of the first phase of insulin secretion (10). It is noteworthy that these glucose levels are well within the targets of our 2013 CDA clinical practice guidelines, reminding us that glucotoxicity may apply to most patients with diabetes, particularly early in the course of the disease. The findings that even very mild hyperglycemia can impede normal insulin secretion and action reminds us of how tightly our body normally controls blood glucose levels in those without dysglycemia, thereby reflecting the biologic importance of optimal glycemic control. Thus, ß-cell dysfunction leads to glucotoxicity, which itself further exacerbates ß-cell function and contributes to the progression of T2DM. As such, early in the course of T2DM, the elimination of glucotoxicity could provide a means for potentially reversing some of the ß-cell dysfunction that drives the natural history of diabetes.
ß-cell dysfunction has both reversible and irreversible components and it is believed that the contribution of these components change over time (7). Early in the course of T2DM, there is greater reversible component of ß-cell dysfunction, but with longer duration of diabetes, there is more irreversible dysfunction.
An example of the impact of reversible ß-cell dysfunction can be seen in the situation where a patient with newly-diagnosed T2DM with A1C ~ 10.0% experiences a profound reduction in glycemia (e.g. to A1C 6.5%) in response to metformin monotherapy. Such a response is indicative of the alleviation of glucotoxicity, yielding an amplification of the anticipated glucose-lowering effect of metformin. As reversibility of ß-cell dysfunction is greatest early in the course of diabetes, attempts at halting the progression of T2DM should be initiated early rather than later.
Lipotoxicity refers to the damaging effects on insulin secretion of chronic exposure to excessive free fatty acids (FFA) (9). As insulin has both glucose-lowering and anti-lipolytic effects, early insulin therapy offers the beneficial effect of reducing exposure of the ß-cells to both excessive glucose and FFAs. However, if alleviation of glucotoxicity and lipotoxicity is to improve ß-cell function, then the insulin therapy needs to be initiated early in the natural history of T2DM when there exists sufficient residual ß-cell mass to make a difference (7, 11).
There have been many studies supporting the use of intensive insulin therapy (IIT) early in the course of T2DM to improve ß-cell function (11-15). After short-term IIT for two to five weeks in early T2DM, the rates of drugfree glycemic remission are:
- 66% at 3 months of follow-up
- 59% at 6 months
- 46% at 12 months (12)
A study by Weng et al looked at patients with newly diagnosed T2DM who were randomized to either continuous subcutaneous insulin infusion (CSII), multiple daily insulin injections (MDI), or oral antidiabetic therapy (OAD). All three groups achieved similar high rates of euglycemia with two to five weeks of treatment and exhibited significant improvement in ß-cell function following these interventions.
However, compared to the OAD group, both insulin groups achieved much higher rates of remission and preservation of first-phase insulin secretion after one year post-intensive intervention. This suggests that greater ß-cell rest by IIT is likely to go beyond glucose lowering effects and could possibly have extended benefits such as anti-inflammatory and anti-apoptosis effects (16).
Overall, studies have shown that when short-term IIT is used in patients with early T2DM, it can improve insulin resistance (IR) and lipid profile (14, 16). This improvement in IR plays a key role in the reversible component of ß-cell dysfunction and the improvement in ß-cell function is important for the long term effect of remission of diabetes (1, 12, 14).
However, this effect of remission of diabetes is not permanent and wanes over time (12). Thus, the next step is clinical trials focusing on trying to maintain this initial beneficial effect of IIT.
Strategies for maintaining the beneficial effect of short-term IIT in early T2DM
These studies support other previous studies showing that short-term IIT, when used in early T2DM, can induce remission of diabetes for up to one to two years, although this effect wanes over time (12).
The ß-cell Evaluation and Sitagliptin Trial (BEST) was a double-blind, randomized controlled trial evaluating the dipeptidyl peptidase 4 (DPP-4) inhibitor sitagliptin. The primary question was the following: in patients with T2DM, can sitagliptin maintain the improvement in ß-cell function initially achieved with short-term IIT? The mean duration of T2DM was six years and all the participants underwent four to eight weeks of IIT before being randomized to either sitagliptin or placebo, both on background of metformin for 48 weeks.
As expected, ß-cell function improved with the short-term IIT before randomization. However at 48 weeks, this improvement in ß-cell function was lost for both the sitagliptin and placebo arms. Thus, sitagliptin was not able to maintain the initial beneficial effect of shortterm IIT (17).
The LIraglutide and ß-cell RepAir (LIBRA) Trial was a double-blind, randomized controlled trial evaluating the glucagon-like peptide-1 (GLP-1) agonist liraglutide. Again, the primary question was the following: in patients with T2DM, can liraglutide maintain the improvement in ß-cell function initially achieved with short-term IIT? In this trial, the mean duration of T2DM was three years and all of the participants underwent four weeks of IIT prior to randomization to either daily liraglutide or placebo injection for 48 weeks. Once again as expected, initial short-term IIT improved ß-cell function. Following the initial ß-cell function improvement with IIT, the liraglutide arm experienced further ß-cell improvement (~50%) which was maintained for the 48 weeks duration of the study. This suggests that further ß-cell function reversal is possible beyond that achieved with insulin alone. However, this ß-cell function improvement was completely lost at two weeks of stopping liraglutide. This suggests that liraglutide did not improve the underlying pathologic process driving ß-cell dysfunction in T2DM (15). It appears that ongoing treatment of liraglutide may be needed to maintain this beneficial effect and that, when used early in T2DM, it could possibly change the natural history of ß-cell decline. Further study would be needed to address this hypothesis.
In the LIBRA Trial (15), both groups achieved excellent glycemic control throughout the study period of one year. In the liraglutide arm, >50% of participants achieved A1C ≤ 6.0% and oral glucose tolerance test results in the non-diabetic range at each three month assessment. Even in the placebo arm, where participants received IIT almost one year prior, 56% of participants had A1C <6.5% at the end of study period even though 68% were on antidiabetic therapy before joining the study.
The use of IIT in early T2DM is safe. In the LIBRA Trial, despite very tight glycemic control, the incidence of hypoglycemia, defined as any capillary blood glucose level below <4.0 mmol/L, was very low and there were no severe hypoglycemia events. This reflects the fact that, in early T2DM, the capacity for endogenous insulin secretion is maintained, enabling the achievement of tight glycemic control without excessive hypoglycemia.
Increase in glycemic variability has been associated with the risk of hypoglycemia and possibly diabetes complications, and is believed to be related to islet dysfunction. In LIBRA participants during their first and last week on IIT, glucose variability was assessed using six-point profiles of self-monitoring of blood glucose (SMBG). Of 61 patients, 55.7% had a reduction in glucose variability. The change in glucose variability was negatively correlated with the change in ß-cell function. In other words, those with greater improvement in ß-cell function improvement had lower glucose variability. Thus, in early T2DM, glycemic variability is modifiable and can be reduced by improving ß-cell function with short-term IIT (18).
Strategies for maintaining the remission of T2DM
The use of IIT in early T2DM is safe and addresses reversible component ß-cell function. The next step, however, is how to maintain this remission of diabetes.
The REmission Studies Evaluating T2DM Intermittent insulin Therapy (RESET IT) Trial is currently underway, testing to see if ß-cell function can be maintained over longer period of time. The RESET IT study is a multi-centre randomized controlled trial to determine whether intermittent IIT can preserve ß-cell function in early T2DM. The strategy used in this study is to treat those with early T2DM with a short course of IIT every three months to preserve ß-cell function. Hence the title “RESET IT” or another analogy might be getting your car battery charged every three months. The concept is to use short-term IIT as both initial induction therapy and maintenance therapy.
Recruitment criteria: Seeking 150 patients with ≤ 5 years duration of T2DM on either no antihyperglycemic therapy or metformin only
Another strategy being tested is whether combination therapy consisting of a GLP-1 agonist and basal insulin may be particularly beneficial to ß-cell function in early T2DM. This strategy is currently being evaluated in the PREserVing ß-cell function with exenAtide and InsuLin (PREVAIL) trial. The PREVAIL trial is a parallel-arm, randomized control trial to determine whether GLP-1 agonist/basal insulin combination therapy can preserve ß-cell function in early T2DM and is also funded by CIHR. This study is recruiting in Toronto.
Recruitment criteria: Seeking 120 patients with ≤ 7 years duration of T2DM on 0-2 antihyperglycemic agents
In conclusion, short-term IIT can be safely implemented in early T2DM to improve ß-cell function and achieve prolonged glycemic remission. However, this effect is not permanent and wanes over time. The RESET IT and PREVAIL are CIHR-funded randomized controlled trials that are evaluating novel strategies on ß-cell function. These trials ultimately may provide a treatment strategy for preserving ß-cell function and thereby modifying the natural history of T2DM.