Betacell

Targeting Beta-Cell Function Early in the Course of Therapy for Type 2 Diabetes Mellitus

Jack L. Leahy, MD
Irl B. Hirsch, MD
Kevin A. Peterson, MD, MPH
Doron Schneider, MD

Excerpt from a consensus statement recently published in the Journal of  Clinical Endocrinology & Metabolism (JCEM)

Index of This Resource:

• B-Cell Science
• Pathogenesis of T2DM
• Manifestations of β-cell Failure in T2DM
• Implications for Treatment
• Preventing, Delaying, and Reversing β-cell Failure 
• Summary
• References

B-Cell Science

Traditionally, Type 2 diabetes mellitus (T2DM) is viewed as a progressive disease. Pathogenesis is complex, characterized by genetic predisposition that—together with metabolic abnormalities associated with body-weight gain, defective insulin secretion and action, and elevated endogenous glucose production—eventually compromise glucose homeostasis (1). Evidence from both human and animal studies suggests that T2DM is characterized by decreased functional β-cell mass that cannot adapt insulin secretion to compensate for increasing insulin resistance driving the development of overt T2DM (2, 3). β-cell function continues declining progressively despite treatment with anti-diabetic medications as well, as highlighted in the 1995 United Kingdom Prospective Diabetes Study (4).

Accumulating evidence suggests this decline may be slowed or even reversed, particularly in early stages of disease (5). Furthermore, new therapeutic classes of diabetes medications act to improve β-cell function, thus potentially altering the course of the disease. The precise role these new therapies might play in treating T2DM, however, has not yet been fully addressed. In fact, despite the primary and pivotal role that β-cells appear to play in disease development and progression, current clinical practice remains heavily focused on insulin resistance.

Pathogenesis of T2DM

Substantial β-cell failure is now believed to occur at an early stage in disease progression, i.e., prior to diagnosis, after which decline accelerates precipitously (2, 14-19). In the United Kingdom Prospective Diabetes Study (UKPDS), for example, β-cell secretory capacity was reduced 50% by the time fasting hyperglycemia was diagnosed (4, 20). Progressive β-cell failure in T2DM stems from both genetic and acquired factors. Genes include those encoding for glucose metabolism proteins, molecules of the insulin signaling pathways, and transcription factors (21, 22).

Normally the β-cell compensatory ability with respect to insulin resistance keeps blood glucose at near-normal levels (2), balancing changes in insulin sensitivity with proportionate changes in β-cell function (23-25). This hyperbolic relationship between insulin sensitivity and insulin secretion is represented on the curve of the “disposition index.” However, impaired compensation in persons with a ß-cell predisposition to T2DM (so-called susceptible β-cells) triggers a “slippery slope,” beginning with imperfect compensation, incipient manifestations of glycemic dysregulation, such as minimally elevated fasting and post-prandial glucose (26), and acquired abnormalities of β-cell mass and function preceding overt T2DM (See Fig 1) (5).

In the classic longitudinal study of normally glucose-tolerant Pima Indians, obese, insulin-resistant subjects who did not progress to T2DM followed the normal disposition curve over time because of normal β-cell compensation while those who progressed to diabetes (“progressors”) started below the curve and declined further as a manifestation of β-cell failure. In this study, progressors exhibited evidence of β-cell dysfunction even before reaching the range of impaired glucose tolerance (IGT), and by the study’s end their insulin secretion had decreased by 78%, with only a 14% decrease in insulin sensitivity. A similar decrease (11%) in insulin sensitivity occurred in nonprogressors, but their insulin secretion increased by 30%, suggesting that the transition from normoglycemia to IGT to diabetes in the progressors resulted from the limited capacity of β-cells to compensate for relatively constant insulin resistance (1) (See Fig. 2).

Progressive β-cell failure in T2DM stems from both genetic and acquired factors. Genes include those encoding for glucose metabolism proteins, molecules of the insulin signaling pathways, and transcription factors (6,13,14,35). Among acquired factors, glucose toxicity, lipotoxicity, increased IAPP deposition, and inflammatory cytokines are most often cited as contributors to β-cell failure (2, 5, 27). In combination, these factors produce β-cell mass and function incapable of responding adequately to increased demand. To elucidate the pathophysiology of both progression and remission of diabetes, Weir et al. proposed a five-stage model (28) (See Table  1)

TABLE 1. PROPOSED STAGES OF β-CELL DYSFUNCTION DURING PROGRESSION TO T2DM*

Adapted from G.C. Weir et al.: Diabetes 50(Suppl 1):S154-S159, 2001 (27).  See original reference for specific information on listed genes and expression changes.  * Gene expression data derived from rodent models.

Although the limited animal and clinical studies available to date support the generalities of this model, additional work is necessary to support the specific staging and evaluate clinical relevance..

Manifestations of β-cell Failure in T2DM

Numerous studies have documented various functional, qualitative, and anatomic manifestations of β-cell failure associated with T2DM that collectively induce diminished responses to oral and intravenous glucose and resulting hyperglycemia (29-31). This diminished insulin release initiates a vicious cycle: prolonged exposure to even modestly elevated glucose has been associated with β-cell desensitization, increased apoptosis, delays in first-phase β-cell response to oral glucose, and attenuated second-phase insulin release (32).

Qualitative defects of insulin release in T2DM include disruption of pulsatile secretion rhythms and processing of the precursor peptide proinsulin to fully active insulin (33-35). Proinsulin processing occurs within the secretory granule, where proinsulin is cleaved into insulin and C-peptide. In non-diabetic individuals, this conversion process is near-complete, leaving approximately 2% of the intact or incompletely cleaved proinsulin precursor molecules in the granules (36, 37). In T2DM, however, less efficient conversion of proinsulin to insulin by β-cells increases this proportion four- to five-fold (38).

Anatomical and cellular abnormalities of pancreatic β-cells also characterize T2DM (39). Normally, islet β-cell mass varies to help balance insulin supply with metabolic demand. The net growth rate is the sum of β-cell replication, size, and neogenesis, minus the rate of β-cell apoptosis (40). In T2DM, however, β-cell apoptosis surpasses replication and neogenesis, likely causing overall β-cell loss. The islets in advancing T2DM tend to be disorganized and misshapen, with amyloid plaques derived from islet amyloid polypeptide (IAPP) (19, 41). In the remaining third, however, this adaptive response is impaired and ß-cell death enhanced, leaving fewer islets containing fewer β-cells and thus a net decrease in mass (19, 39, 42).
 

Because morphologic assessment of human β-cells can only occur postmortem, most knowledge comes from rodent studies, and information about specific anatomic and cellular changes associated with T2DM in humans remains relatively limited. From the latter perspective, the postmortem study of human pancreatic tissue by Butler et al. (19) is noteworthy.  This study examined pancreatic tissue from autopsies of 91 obese individuals, 41 with T2DM, 15 with impaired glucose tolerance, and 35 without diabetes, as well as tissue from 33 lean subjects, 16 with and 17 without T2DM. β-cell volume in individuals with T2DM and prediabetes was significantly less than weight-matched nondiabetic subjects (See Fig. 3). Notably, the rate of new islet formation was sustained in patients with longstanding diabetes, arguably suggesting the potential of novel therapies inhibiting apoptosis or enhancing β-cell neogenesis and replication (19, 27). However, noninvasive tracking methods for ß-cell mass will be needed to correlate loss with specific functional changes or physiologic types (2).

Preventing, Delaying, and Reversing β-cell Failure

Animal studies support the idea of β-cell mass and/or function as modifiable parameters, especially in earlier stages of the disease (27, 43, 44). In vitro studies have similarly suggested that the shorter the period of antecedent glucose exposure, the more likely cultured β-cells are to recover full function (45). Clinical evidence is suggestive as well. The Finnish Diabetes Prevention Study and the US Diabetes Prevention Program, both showed a 58% reduction in diabetes less incidence among individuals with IGT treated with diet and exercise for ∼3 years (46, 47). Also, diabetes rates in pre-diabetic patients treated with metformin for the same period declined by 31% (46), and, in high-risk patients treated with acarbose in the STOP-NIDDM randomized trial, by 25% (48). Although these findings are consistent with the concept that early intervention to lower glucose levels may check disease progression, they may reflect delays in, rather than prevention of, progression, because cumulative incidence rates of diabetes rose at the end of these studies in both treatment and control groups.

Associations between acute glucose lowering and improved acute insulin secretory responses more directly suggest improved β-cell function. Comparing and assessing effects of pharmacological therapies used to control hyperglycemia  on β-cell function is necessarily inferential, given lack of any universal measure (49). Nonetheless, observations from several small, relatively short-term trials in newly diagnosed patients suggest an association between β-cell preservation and more durable glycemic control.  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 (50). 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 (51). 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, although the attrition of so many patients beyond the three-month check may skew these figures. 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 (52). 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 (53).  Although these findings are intriguing, larger, controlled studies will be required to document conclusively significant durable recovery of β-cell function.

Among well-established therapies, thiazolidinediones (TZDs) have been shown in animal studies to prevent the loss of net β-cell death (54), and, in clinical trials appear to improve β-cell function in patients with T2DM (10, 55) as well as induce durable glycemic control (10, 56, 57). The double-blind, randomized, controlled ADOPT study compared durability of glycemic control among 4,360 patients recently diagnosed with T2DM treated with rosiglitazone, metformin, or glyburide for a median of four years. Maintenance of glycemic control was better after five years with rosiglitazone monotherapy than with either metformin or glyburide, although study design did not distinguish between reduced insulin resistance and improved mass or intrinsic β-cell function. In another study of 17 subjects with T2DM, rosiglitazone added to a failing regimen of sulfonylurea and metformin for six months improved β-cell function, as evidenced by restored first-phase insulin response, improvement in the disposition index, and decreased proinsulin-to-insulin ratio (58). The DREAM (Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication) study demonstrated a 62% decrease in progression to T2DM among patients with impaired glucose tolerance and/or impaired fasting glucose receiving rosiglitazone (59), and the ACT NOW (Actos Now for Prevention of Diabetes) trial showed a reduction of 81% with pioglitazone (14). In ACT-NOW, changes in the disposition index indicated both improved insulin sensitivity and β-cell function. Results from the TRIPOD (Troglitazone in Prevention of Diabetes) and PIPOD (Pioglitazone in Prevention of Diabetes) studies of women with prior gestational diabetes (60, 61) suggest similar conclusions.

Recent clinical studies also suggest that incretin therapies may directly target β-cell failure, although, as with the thiazolidinediones, 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 ( 62). 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 (63), as is the secretion of GLP-1 in response to oral glucose (64). 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 (65-72), as well as numerous direct effects on the gastrointestinal, cardiac, and central nervous systems (67, 73-83). 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 (84-86), and preclinical studies indicate that direct activation of distinct G protein-coupled receptors expressed on islet β-cells may underlie these effects (87-91). However, whether those effects occur in humans is unknown.

Several clinical trials have shown that the DPP-IV inhibitors sitagliptin and vildagliptin, improve both postprandial and fasting β-cell function in patients with T2DM for up to 24 weeks (92-98). 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 (99). 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 (100). Another GLP-1 receptor agonist, liraglutude 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 (101). With a significantly longer half-life than exenatide, liraglutide can be dosed once daily (102, 103). Once-daily subcutaneous administration for 1 week significantly lowered overall glycemia while improving first-phase insulin response and nearly doubling the disposition index (104). Durability of any of these effects remains unestablished; a 1-year study of metformin-treated T2DM patients showed a C-peptide response to arginine during hyperglycemia 2.46-fold greater after 52 weeks of exenatide than with insulin glargine, but β-cell function and glycemic control returned to pretreatment values after cessation of therapy, suggesting a need for ongoing treatment (105).

Implications for Treatment

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 also require considering hypoglycemic frequency, mechanisms of action, adverse-event profiles, tolerability, failure rate, and cost (106,107). Ultimately, too, it 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 deleterious effects of chronic hyperglycemia on β-cell function, deserves greater emphasis (15, 108). Furthermore, more refined understanding of the complex interplay between insulin resistance in the muscle and liver with β-cell failure, as well as the role of accelerated lipolysis, incretin deficiency/resistance, hyperglucogonemia, increased glucose reabsorption, and insulin resistance in the brain suggests a need to move toward an integrated, multi-organ approach to treatment that addresses β-cell failure as well as insulin resistance will be essential as clinical practice increasingly incorporates genetics and focuses on durability of therapy.

Ideally, too, the evolving understanding of T2DM’s natural history will foster the emergence of a pathophysiologically-based paradigm for medical decision-making that aligns basic research to clinical practice. 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 glycemic goals (106, 109,110). DeFronzo (15) recently proposed a treatment algorithm specifically targeting β-cell failure early in disease progression. This algorithm combines diet and exercise with multiple drugs to correct and possibly reverse the progressive β-cell failure that already is well-established in people with IGT (15).

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% (11, 12, 111). In 2004, Grant et al. (111) studied the process by which physicians chose medications for T2DM by surveying 886 academic generalists (response rate 30%) and specialists (response rate 23%) currently managing T2DM patients. Tellingly, respondents frequently cited overall assessment of the patient's health/comorbidity, hemoglobin A1C level, and patient's adherence behavior as major considerations in determining therapy but not expert guidelines/hospital algorithms or patient age (111).

Summary

Declining β-cell function in the presence of increasing hyperglycemia and relatively constant insulin resistance characterizes the pathogenesis of T2DM. Recent studies suggest that this 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.

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