GLP-1's Function in Preserving B-cells

Observations from several small, relatively short-term trials in newly diagnosed patients suggest an association between β-cell preservation and more durable glycemic control. Improvements to β-cell function can be seen with more timely treatments to gain euglycemia.

One small, uncontrolled trial, for example, found that nearly half of the 16 newly diagnosed patients with severe hyperglycemia who underwent a 2- to 3-week course of multiple daily insulin injections maintained glycemic control for one year on diet therapy alone, with those achieving normoglycemia on insulin most likely to control glucose levels through diet measures alone.² In another uncontrolled trial, two weeks of continuous subcutaneous insulin infusion (CSII) therapy, followed by dietary treatment alone, established near-normal glycemic control in 13 newly diagnosed T2DM patients who had previously failed dietary measures, nine of whom achieved near-normal glycemic control for 9 to more than 50 months after the initial CSII. ³ In a similar protocol, 126 out of 138 newly diagnosed patients with fasting glucose >200 mg/dL achieved optimal glycemic control within 6.3 ± 3.9 days. The percentage of participants maintaining near-normal glucose levels at the 3rd, 6th, 12th, and 24th months were 72.6 (82 of 113), 67.0 (61 of 91), 47.1 (32 of 68), and 42.3% (11 of 26) respectively. Of the returning patients, however, those who maintained glycemic control for over a year had the greatest recovery of β-cell function when assessed immediately after CSII, as indicated by homeostasis model assessment of β-cell function (HOMA-B) and the area under the curve (AUC) of insulin, as well as a higher acute insulin response ⁴ A multicenter, randomized expansion of this study to over 350 newly diagnosed patients confirmed these findings and suggested that early intensive insulin therapy may facilitate recovery and maintenance of B-cell function and protracted glycemic remission better than oral hypoglycemic agents for at least 1 yr after diagnosis. ⁵ Although these findings are intriguing, larger, controlled studies will be required to document conclusively significant durable recovery of β-cell function.

Recent clinical studies also suggest that incretin therapies may directly target β-cell failure, whether these effects persist beyond duration of treatment remains unproven. These relatively new drug classes include the glucagon-like peptide-1 (GLP-1) receptor agonists, which provide pharmacologic replacement of that incretin peptide, and the dipeptidyl peptidase-IV (DPP-IV) inhibitors, which enhance endogenous levels of incretins by blocking their inactivation. Like the short-lived gut-derived hormone GLP-1 on which they are based, the GLP-1 receptor agonists stimulate insulin secretion in a glucose dependent manner. They thus mimic the natural "incretin effect" (the difference in response to oral vs. intravenous glucose load), which is markedly reduced in people with T2DM, as is the secretion of GLP-1 in response to oral glucose. Also these agents recreate the full spectrum of natural GLP-1's functional effects, which include not only improving β-cell function and insulin sensitivity but also increasing glucose-dependent insulin secretion, lowering glucagon secretion, inhibiting gastric emptying, reducing appetite, and decreasing caloric intake, as well as numerous direct effects on the gastrointestinal, cardiac, and central nervous systems. In addition, GLP-1 and its related analogs have been shown in animal models to increase β-cell mass by inhibiting apoptosis and promoting proliferation of islet cells and differentiation of non-insulin-secreting cells. ^6,7,8 However, whether those effects occur in humans is unknown.

Several clinical trials have shown that the DPP-IV inhibitors improve both postprandial and fasting β-cell function in patients with T2DM for up to 24 weeks. ^9-10 Another recent study using a homeostasis model assessment found that first- and second-phase insulin responses, as well as both fasting and stimulated β-cell function, returned to normal after overnight administration of GLP-1.¹¹ Similarly, intravenous administration of the GLP-1 receptor agonist, exenatide, maintained for 30 minutes, restored normal insulin secretory pattern after glucose challenge in T2DM patients lacking a first-phase insulin secretion in the absence of exenatide. Another GLP-1 receptor agonist, liraglutide administered via a single subcutaneous injection to adults with well-controlled T2DM showed increased insulin and C-peptide levels and dramatically improved insulin secretory response attributed to restored β-cell responsiveness.¹² With a significantly longer half-life than exenatide, liraglutide can be dosed once daily. Once-daily subcutaneous administration for 1 week significantly lowered overall glycemia while improving first-phase insulin response and nearly doubling the disposition index.¹³

Regardless of whether these potential effects on β-cells can be maintained over time, determining potential clinical value of any of these pharmacologic approaches will be imperative to determine whether preserving β-cell mass and/or function improves morbidity and mortality rates, reduces complications, and/or improves quality of life for people with T2DM.

Nonetheless, the increasing recognition that β-cell failure occurs much earlier and severely than commonly believed suggests that regular glycemia screening and identification of patients at metabolic risk, as well as prompt and aggressive intervention to stem the cumulative effects of chronic hyperglycemia on β-cell function, deserves greater attention. Several recently advocated treatment algorithms already recognize that the progressive nature of β-cell decline necessitates intensifying therapy over time through stepwise treatment to achieve and maintain euglycemia.

Current clinical practice often differs markedly from such evidence-based treatment guidelines. Under most scenarios today, transitions from one diabetes regimen to another occur slowly, so that fewer than 60% of treated T2DM patients meet the American Diabetes Association A1C goal of less than 7%.

In summary, recent studies suggest that declining β-cell function in the presence of increasing hyperglycemia and relatively constant insulin resistance characterizes the pathogenesis of T2DM, and that the process begins early in the disease's natural history, accelerates markedly after reaching a compensatory threshold, drives the progression of the disease, and is potentially reversible, particularly in the early stages. Achieving and maintaining recommended glycemic targets is difficult for many patients due to this progressive decline, delays in intensifying therapy, and the interplay of patient, clinician, and systemic factors impeding diabetes management in primary care. However, new evidence suggests that early intervention to improve metabolic control may improve β-cell function. Although lasting effects and ultimate clinical value of these interventions remain to be proven, continued multidisciplinary efforts to realign treatment with T2DM's natural history, including addressing β-cell dysfunction before insulin secretory capacity is permanently lost, already show promise in promoting safer, more effective care for this vulnerable population and warrant organized educational efforts to promote pathophysiology-based clinical practice by primary care physicians.

References:

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