HeConnection-Cure-Beta Cell PreservationBeta Cell Preservation, Replication, Regeneration in Diabetes: a Realistic Therapeutic Target?

(Excerpts: Meier, J.J. Beta cell mass in diabetes: a realistic therapeutic target? Diabetologia (2008) 51:703–713)

While it has long been held that type 1 diabetes results from an irreversible loss of beta cells, and that type 2 diabetes is primarily caused by impaired insulin action, there is now increasing evidence linking both types of diabetes to defects in beta cell mass and insulin secretion. Furthermore, the former dogma that beta cells are irreversibly incapable of replicating during adult life has been challenged over the past years. These advances offer the potential to target beta cell preservation, replication, regeneration as future diabetes treatments.

In type 1 diabetes, beta cell loss occurs as a consequence of immune-mediated beta cell destruction [1, 2, 31], although the trigger(s) for this process remains unknown. This depletion within the islet is beta cell-specific, perhaps mediated through insulin serving as an antigen attracting auto-reactive T lymphocytes and macrophages. Similar to the pathogenesis of type 2 diabetes, the destruction of beta cells in patients with type 1 diabetes seems to precede the clinical manifestation of the disease, and impaired insulin secretion can be detected several years prior to the onset of hyperglycemia [32].

Based on histological studies of pancreas specimens from patients with new-onset type 1 diabetes, beta cell mass is reduced by ~80–90% at this time [1, 33–35]. Interestingly, the degree of beta cell dysfunction at this time often exceeds the percentage beta cell loss [36–38], suggesting additional functional impairment in insulin secretion in these patients. Both beta cell mass and function further decline with increasing diabetes duration [33, 37, 39], but preserved C-peptide responses have been reported even after several years of type 1 diabetes [40, 41].

There is now evidence from several lines of research that some beta cell regeneration may occur even in people with long-term type 1 diabetes [2]. Even though beta cell mass is markedly diminished in people with long-standing type 1 diabetes, some beta cells can be detected several decades after disease onset [1, 2]. These cells have an increased frequency of apoptosis (cell death), implying that beta cell formation must be occurring even after several years of type 1 diabetes [2]. This hypothesis has been supported by reports of restoration of beta cell mass after the onset of hyperglycemia in NOD mice [42], and of a marked increase in beta cell replication at the time of diabetes onset in mice and in humans [36, 38].

The potential for restoration of beta cell mass

The beta cell deficit in both type 1 and type 2 diabetes provides a rationale for novel therapeutic strategies aimed at restoring, or at least preventing further loss of beta cell mass. In fact, enhancement of endogenous insulin secretion may theoretically provide several advantages over the administration of exogenous insulin:

  1. Endogenous insulin secretion works much faster than exogenous insulin [43, 44];
  2. Under physiological circumstances, insulin is secreted in distinct pulses occurring at ~4–5 min intervals [45], and endogenous insulin secretion is regulated in a strictly glucose-dependent manner [46];
  3. Alpha cell secretion is controlled by the pulsatile release of insulin from islet beta cells [18, 47];
  4. Endogenous pulsatile insulin secretion has a direct effect on hepatic (liver) glucose metabolism, whereas exogenous insulin replacement primarily acts on peripheral insulin-sensitive tissues.

Strategies for beta cell regeneration

Embryonic stem cells

One potential way of replenishing beta cell mass is the generation of insulin-secreting cells from embryonic stem cells [4]. This field has advanced over recent years, in particular as a result of the development of more specific incubation regimens [48]. Such human embryonic stem cell-derived preparations have been shown to release insulin upon challenge, but reported to be particularly unresponsive to glucose stimulation [48]. In addition to this lack of glucose responsiveness, ethical hurdles associated with the generation of insulin-secreting cells from human embryos complicate the further development of this approach. It is as yet impossible to control the proliferative activity of such cells, which poses a risk for tumour formation [4].

Beta cell replication and islet neogenesis

An alternative strategy for the restoration of beta cell mass in patients with diabetes is to foster beta cell regeneration from endogenous sources [4]. Some evidence suggests that beta cell mass is dynamic and capable of undergoing adaptive changes in response to different secretory demands [52]. In humans, beta cell mass increases by ~50% in obesity [3], and both insulin secretion and beta cell mass have been shown to increase in pregnant women [53, 54]. Likewise, beta cell mass in rodents increases by ~2.5-fold towards the end of pregnancy, and is rapidly decreased through increased apoptosis and reduced replication postpartum [52, 55, 56].

There is ongoing debate as to the potential origin of new beta cells in adults, and two major pathways have been proposed. On the one hand, replication of pre-existing beta cells in the pancreas has been convincingly demonstrated in adult mice [57, 58], rats [59, 60] and humans [3, 36, 61, 62], and recent lineage tracing studies indicated that new beta cell formation in postnatal mice exclusively results from the replication of existing beta cells [57].

On the other hand, the close association between exocrine ducts and beta cells has been interpreted as evidence that beta cells might also arise from stem cells residing in the ductal epithelium [63, 64]. Significant increases have been described in rodents after partial pancreatectomy [63, 66] and after prolonged hyperglycemia or glucagon-like peptide 1 (GLP-1) treatment [67, 68]. However, the presence and quantitative significance of new beta cell formation from exocrine ducts remains to be proven.

There is little doubt that beta cell replication continues over a lifetime. However, the overall frequency of beta cell replication is extremely low in the adult pancreas [59].

Despite the slow rate of beta cell turnover under normal steady-state conditions, there appears to be a remarkable capacity for increased proliferation in situations of high secretory demand. In rodents, beta cell replication increases by approximately five- to tenfold after partial pancreatectomy, during pregnancy, during chronic glucose infusion and after treatment with GLP-1 analogues [63, 66], thereby illustrating the remarkable plasticity of the endocrine pancreas in rodents. In humans, the overall capacity for beta cell replication is much lower than in rodents, and very few replicating beta cells (one cell in ~50 islets of ~100 beta cells each per cross-section) can be found in adult human pancreas [3]. There is, however, a capacity for increased beta cell replication in humans. Beta cell replication has been reported to be more than ten times higher in human pancreas adjacent to gastrin-producing tumours [62] and in the pancreas of a patient presenting with the recent-onset type 1 diabetes [36].

The different turnover rates of beta cells in rodents and in humans have important implications for interpreting studies designed to replenish beta cell mass.

Therapeutic strategies to maintain or restore beta cell mass in diabetes

As a result of the growing interest in beta cell regeneration as a potential cure for diabetes, a number of different treatment strategies aimed at increasing beta cell mass have been evaluated. These include:

  1. Inhibition of beta cell apoptosis (cell death) and/or stimulation of beta cell regeneration in beta cell lines and/or isolated (human) islets in vitro;
  2. Increasing beta cell mass in animal models (primarily rats and mice) in vivo; and
  3. Functional improvements (or at least preservation) of insulin secretion in long-term studies in patients with diabetes in vivo.

Importance of beta cell rest and exhaustion for diabetes therapy

When evaluating the effects of glucose-lowering treatment regimens on beta cell turnover, one key aspect determining the fate of the beta cells may be the individual’s demand for insulin secretion. There is some evidence from in vitro studies that constant stimulation of insulin secretion by either prolonged high glucose exposure or sulfonylurea treatment may result in beta cell death [80, 81]. These potentially detrimental effects of sulfonylureas may serve to explain the relatively high rates of beta cell failure during sulfonylurea therapy in the a Diabetes Outcome Progression Trial (ADOPT [82, 83]. While beta cell exhaustion may potentially accelerate the loss of beta cells in type 2 diabetes, induction of beta cell rest, i.e. the temporary inhibition of insulin secretion, appears to confer a certain degree of beta cell protection. In isolated human islets, temporary inhibition of insulin secretion using potassium channel openers has led to subsequent improvement of glucose-induced insulin secretion, increased islet insulin content, and inhibition of beta cell apoptosis [29, 85].

Health-e-Solutions comment: The most direct way to induce beta cell rest is to reduce insulin demand by decreasing dietary glycemic load.

From a clinical point of view, the simplest way of inducing beta cell rest is to reduce the peripheral insulin demand by either improving insulin sensitivity (e.g. through physical activity or pharmacologically) or by lowering blood glucose levels through the administration of exogenous insulin. In a prospective trial on patients with type 2 diabetes, induction of beta cell rest induced by bedtime administration of NPH insulin resulted in significant improvements in endogenous insulin secretion in response to glucose [75]. Likewise, in a study that compared insulin with glibenclamide over 2 years, recently diagnosed patients with type 2 diabetes treated with insulin exhibited a significantly greater endogenous insulin secretory response and a lower proinsulin: insulin ratio [87]. Nevertheless, as yet, there is no direct evidence for the preservation of beta cell mass by either metformin, glitazones or exogenous insulin in patients with type 2 diabetes in vivo.

A number of glucose-lowering agents (e.g. incretin mimetics, dipeptidylpeptidase 4 [DPP-4] inhibitors) have been suggested to prevent beta cell apoptosis, but their long-term effects on beta cell mass in patients with diabetes remain to be elucidated.

Outlook

In response to the increased recognition of the important role of beta cell mass in the development of diabetes interest has grown in targeting beta cell mass for the treatment for diabetes. A number of recent studies have suggested that beta cell mass might be restored by fostering endogenous beta cell replication, combined with concomitant inhibition of apoptosis.

Debate is ongoing as to the potential effects of various glucose-lowering treatments on beta cell death and proliferation, and some drugs have been proposed to accelerate beta cell loss (e.g. glibenclamide), whilst others have been suggested to be somewhat protective (e.g. GLP-1 receptor agonists, DPP-4 inhibitors). However, before any of these treatment regimens can be accepted as safely modulating beta cell turnover, changes in beta cell mass need to be demonstrated in patients with diabetes. It is hoped that future long-term trials involving metabolic testing in patients with diabetes will determine changes in beta cell mass in response to various glucose-lowering treatment regimens. Such information will enable physicians to not only focus on glucose control, but perhaps also to modulate the natural progression of diabetes.

Health-e-Solutions Comment: The demand for insulin, either exogenous or endogenous, is greatly affected by our diet. By focusing on foods that are very low-glycemic in #TheRomanDiet, the demand on beta cell insulin secretion may be reduced in those with sufficient beta cell mass, thereby providing a measure of beta cell rest. We call it “giving the pancreas a vacation.”

We would argue that maintaining normal blood glucose levels, with both endogenous and exogenous (if necessary) insulin is the optimal way of preserving remaining beta cells and allowing for natural beta cell replication to flourish. However, the fly in the ointment may be persistent autoimmune attack that would potentially destroy any newly formed beta cells. Even so, we know that people with type 1 diabetes for decades still give evidence of having functioning beta cell mass. Perhaps diet and lifestyle changes can mitigate the autoimmune attack by putting the body in a position of strength to correct the errant attack and allow for beta cell mass to improve.

We can dream, can’t we?

We’d like to see you have success. Contact us today to schedule a consult. Or purchase our video workshop course and get on the road today toward better health, and to #ControlBloodSugarNaturally. People who have followed our natural, healthy lifestyle solutions have:

  • Health-e-Solutions Framework of H.O.P.E.-Beta Cell PreservationDecreased their HbA1c percentage
  • Reduced or eliminated insulin requirements,
  • Reversed symptoms and complications
  • Improved insulin sensitivity
  • Improved fasting and post-prandial blood glucose levels
  • Increased c-peptide secretion and insulin production
  • Decreased or eliminated insulin antibodies
  • Normalized their weight

(* results may vary)

With our #FrameworkOfHOPE, we help you establish a lifestyle foundation that may stop or reverse disease progression and complications naturally, and reduce #InsulinDemand and other medication requirements. Get off the roller coaster of high and low blood sugars, and get on the rolling plains of normal, control.

Resources:

1. Gepts W (1965) Pathologic anatomy of the pancreas in juvenile diabetes mellitus. Diabetes 14:619.663

2. Meier JJ, Bhushan A, Butler AE, Rizza RA, Butler PC (2005) Sustained beta cell apoptosis in patients with long-standing type 1 diabetes: indirect evidence for islet regeneration? Diabetologia 48:2221.2228

3. Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC (2003) Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 52:102.110

4. Meier JJ, Bhushan A, Butler PC (2006) The potential for stem cell therapy in diabetes. Pediatr Res 59:65R.73R

5. Robertson RP (2000) Successful islet transplantation for patients with diabetes.fact or fantasy? N Engl J Med 343:289.290

18. Meier JJ, Kjems LL, Veldhuis JD, Lefebvre P, Butler PC (2006) Post prandial suppression of glucagon secretion depends on intact pulsatile insulin secretion: Further evidence for the intraislet insulin hypothesis. Diabetes 55:1051.1056

29. Maedler K, Storling J, Sturis J et al (2004) Glucose- and interleukin-1ƒÀ-induced beta-cell apoptosis requires Ca2+ influx and extracellular signal-regulated kinase (ERK) 1/2 activation and is prevented by a sulfonylurea receptor 1/inwardly rectifying K+ channel 6.2 (SUR/Kir6.2) selective potassium channel opener in human islets. Diabetes 53:1706.1713

31. Kloppel G, Drenck CR, Oberholzer M, Heitz PU (1984) Morphometric evidence for a striking B cell reduction at the clinical onset of type 1 diabetes. Virchows Arch A Pathol Anat Histopathol 403:441.452

32. Tsai EB, Sherry NA, Palmer JP, Herold KC (2006) The rise and fall of insulin secretion in type 1 diabetes mellitus. Diabetologia 49:261.270

33. Madsbad S (1983) Prevalence of residual B cell function and its metabolic consequences in type 1 (insulin-dependent) diabetes. Diabetologia 24:141.147

34. Pipeleers D, Ling Z (1992) Pancreatic beta cells in insulindependent diabetes. Diabetes Metab Rev 8:209.227

35. Butler AE, Galasso R, Meier JJ, Basu R, Rizza RA, Butler PC (2007) Modestly increased beta cell apoptosis but no increased beta cell replication in recent-onset type 1 diabetic patients who died of diabetic ketoacidosis. Diabetologia 50:2323.2331

36. Meier JJ, Lin JC, Butler AE, Galasso R, Martinez DS, Butler PC (2006) Direct evidence of attempted beta cell regeneration in an 89-year old patient with recent onset type 1 diabetes. Diabetologia 49:1838.1844

37. The Diabetes Control and Complications Trial Research Group (1987) Effects of age, duration and treatment of insulin-dependent diabetes mellitus on residual beta-cell function: observations during eligibility testing for the Diabetes Control and Complications Trial (DCCT). J Clin Endocrinol Metab 65:30.36

38. Sreenan S, Pick AJ, Levisetti M, Baldwin AC, Pugh W, Polonsky KS (1999) Increased beta-cell proliferation and reduced mass before diabetes onset in the nonobese diabetic mouse. Diabetes 48:989.996

39. Lohr M, Kloppel G (1987) Residual insulin positivity and pancreatic atrophy in relation to duration of chronic type 1 (insulin-dependent) diabetes mellitus and microangiopathy. Diabetologia 30:757.762

40. Madsbad S, Krarup T, Reguer L, Faber OK, Binder C (1981) Effect of strict blood glucose control on residual B cell function in insulin-dependent diabetics. Diabetologia 20:530.534

41. The Diabetes Control and Complications Trial Research Group (1998) Effect of intensive therapy on residual beta-cell function in patients with type 1 diabetes in the diabetes control and complications trial. A randomized, controlled trial. Ann Intern Med 128:517.523

42. Chatenoud L, Thervet E, Primo J, Bach JF (1994) Anti-CD3 antibody induces long-term remission of overt autoimmunity in nonobese diabetic mice. Proc Natl Acad Sci USA 91:123.127

43. Pfeifer MA, Halter JB, Porte D Jr (1981) Insulin secretion in diabetes mellitus. Am J Med 70:579.588

44. Bruttomesso D, Pianta A, Mari A et al (1999) Restoration of early rise in plasma insulin levels improves the glucose tolerance of type 2 diabetic patients. Diabetes 48:99.105

45. Porksen N, Nyholm B, Veldhuis JD, Butler PC, Schmitz O (1997) In humans at least 75% of insulin secretion arises from punctuated insulin secretory bursts. Am J Physiol 273:E908.E914

46. Matschinsky F, Liang Y, Kesavan P et al (1993) Glucokinase as pancreatic beta cell glucose sensor and diabetes gene. J Clin Invest 92:2092.2098

47. Zhou H, Tran PO, Yang S et al (2004) Regulation of alpha-cell function by the beta-cell during hypoglycemia in Wistar rats: the gswitch-offh hypothesis. Diabetes 53:1482.1487

48. DfAmour KA, Bang AG, Eliazer S et al (2006) Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells. Nat Biotechnol 24:1392.1401 Diabetologia (2008) 51:703.713 711

52. Sorenson RL, Brelje TC (1997) Adaptation of islets of Langerhans to pregnancy: beta-cell growth, enhanced insulin secretion and the role of lactogenic hormones. Horm Metab Res 29:301.307

53. Kjos SL, Buchanan TA (1999) Gestational diabetes mellitus. N Engl J Med 341:1749.1756

54. Van Assche FA, Aerts L, De Prins F (1978) A morphological study of the endocrine pancreas in human pregnancy. Br J Obstet Gynaecol 85:818.820

55. Hellerstrom C, Swenne I (1991) Functional maturation and proliferation of fetal pancreatic beta-cells. Diabetes 40(Suppl 2):89.93

56. Scaglia L, Cahill CJ, Finegood DT, Bonner-Weir S (1997) Apoptosis participates in the remodeling of the endocrine pancreas in the neonatal rat. Endocrinology 138:1736.1741

57. Dor Y, Brown J, Martinez OI, Melton DA (2004) Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation. Nature 429:41.46

58. Butler AE, Janson J, Soeller WC, Butler PC (2003) Increased betacell apoptosis prevents adaptive increase in beta-cell mass in mouse model of type 2 diabetes: evidence for role of islet amyloid formation rather than direct action of amyloid. Diabetes 52:2304.2314

59. Teta M, Long SY, Wartschow LM, Rankin MM, Kushner JA (2005) Very slow turnover of ƒÀ-cells in aged adult mice. Diabetes 54:2557.2567

60. Finegood DT, Scaglia L, Bonner-Weir S (1995) Dynamics of betacell mass in the growing rat pancreas. Estimation with a simple mathematical model. Diabetes 44:249.256

61. Meier JJ, Butler AE, Galasso R, Butler PC (2006) Hyperinsulinemic hypoglycemia after gastric bypass surgery is not accompanied by islet hyperplasia or increased beta-cell turnover. Diabetes Care 29:1554.1559

62. Meier JJ, Butler AE, Galasso R, Rizza RA, Butler PC (2006) Increased islet beta cell replication adjacent to intrapancreatic gastrinomas in humans. Diabetologia 48:2689.2696

63. Bonner-Weir S, Baxter LA, Schuppin GT, Smith FE (1993) A second pathway for regeneration of adult exocrine and endocrine pancreas. A possible recapitulation of embryonic development. Diabetes 42:1715.1720

64. Bouwens L, Pipeleers DG (1998) Extra-insular beta cells associated with ductules are frequent in adult human pancreas. Diabetologia 41:629.633

66. Peshavaria M, Larmie BL, Lausier J et al (2006) Regulation of pancreatic beta-cell regeneration in the normoglycemic 60% partial-pancreatectomy mouse. Diabetes 55:3289.3298

67. Bonner-Weir S, Deery D, Leahy JL, Weir GC (1989) Compensatory growth of pancreatic beta-cells in adult rats after short-term glucose infusion. Diabetes 38:49.53

68. Xu G, Stoffers DA, Habener JF, Bonner-Weir S (1999) Exendin-4 stimulates both beta-cell replication and neogenesis, resulting in increased beta-cell mass and improved glucose tolerance in diabetic rats. Diabetes 48:2270.2276

75. Cusi K, Cunningham GR, Comstock JP (1995) Safety and efficacy of normalizing fasting glucose with bedtime NPH insulin alone in NIDDM. Diabetes Care 18:843.851

80. Efanova IB, Zaitsev SV, Zhivotovsky B et al (1998) Glucose and tolbutamide induce apoptosis in pancreatic beta-cells. A process dependent on intracellular Ca2+ concentration. J Biol Chem

273:33501.33507

81. Maedler K, Carr RD, Bosco D, Zuellig RA, Berney T, Donath MY (2005) Sulfonylurea induced beta-cell apoptosis in cultured human islets. J Clin Endocrinol Metab 90:501.506

82. Matthews DR, Cull CA, Stratton IM, Holman RR, Turner RC (1998) UKPDS 26: sulphonylurea failure in non-insulin-dependent diabetic patients over six years. UK Prospective Diabetes Study (UKPDS) Group. Diabet Med 15:297.303

83. Kahn SE, Haffner SM, Heise MA et al (2006) Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 355:2427.2443

85. Ritzel RA, Hansen JB, Veldhuis JD, Butler PC (2004) Induction of ƒÀ-cell rest by a Kir6.2/SUR1-selective KATP-channel opener preserves ƒÀ-cell insulin stores and insulin secretion in human islets cultured at high (11 mM) glucose. J Clin Endocrinol Metab 89:795.805

56:2016.2027

87. Alvarsson M, Sundkvist G, Lager I et al (2003) Beneficial effects of insulin versus sulphonylurea on insulin secretion and metabolic control in recently diagnosed type 2 diabetic patients. Diabetes Care 26:2231.2237