1 BETA-CELL FAILURE IN DIABETES AND PRESERVATION BY ...

More documents

Recommendations

Info

24 Optimal metabolic control, especially early intensive glycemic control, plays a role in the prevention of progressive beta-cell dysfunction and possibly destruction of the beta- cells with worsening of diabetes. Many reports have shown that induction of normoglycemia in DM2 results in both improved beta-cell function and insulin resistance (90, 91). Rarely, however, has a prolonged benefit been demonstratedwith virtually all patients becoming hyperglycemic again after a few weeks (92, 93). Until recently it was unknown whether such outcomes pertained to new-onset DM 2, although patients having failed diet therapy may show a good response to a short period of intensive insulin therapy by continuous subcutaneous insulin infusion :CSII (94). Ryan et al (84) recently reported that, in 16 severe (mean fasting plasma glucose of 239 mg/dl) newly diagnosed DM2 patients, a 2 to 3 weeks` course of intensive insulin therapy by multiple daily insulin injection (NPH + regular) was able to maintain good glycemic control at 1 year in 7 of the subjects on diet therapy alone, whilst 8 required oral hypoglycemic agent and 1 required insulin therapy. The distinguishing features of those who did not require oral agents or insulin treatment were that they required less insulin during the active insulin therapy phase (0.37±0.05 vs. 0.73±0.07 units/kg/day) and were able to attain a lower fasting serum glucose at the end of the period of insulin therapy (106±5 vs. 139±7 mg/dl) . It is interesting to highlight that the majority of the study patients (15/16) had an evident recovery of the AUC insulin (oral glucose tolerance test) after the end of insulin therapy, being dramatically higher than study entry values associated with a significant reduction in AUC glucose by year end, probably related to the correction of gluco- and lipotoxicity (significant reduction in triglycerides and FFAs). Thus, the potential benefits of early, aggressive intervention with insulin therapy to counter both beta-cell dysfunction (and insulin resistance) must be considered: effects of insulin therapy against chronic hyperglycemia and lipotoxicity-induced apoptosis of the beta-cells. In a similar study (85), 138 newly diagnosed DM2s with fasting glucose >200 mg/dl were hospitalized and treated with CSII for 2 weeks.After CSII the patients were followed longitudinally on diet alone. Optimal glucose control was achieved within 6.3±3.9 days in 126 patients. The remission rates (percentage of individuals maintaining near euglycemia) at the third, sixth, twelfth and twenty fourth month were 72.6, 67.0, 47.1 and 42.3%, respectively. Patients who maintained glycemic control > 12 months (remission group) had
25 greater recovery of beta-cell function than those who did not (non-remission group) when assessed immediately after CSII. Homeostasis model assessment of beta-cell function (HOMA-beta) and AUCinsulin during IVGTT as well as change in acute insulin response (AIR) were significantly higher in the remission group. Furthermore, proinsulin decreased highly significantly, thus the proinsulin-to-insulin ratio was also reduced highly significantly (indication of an improvement in the quality of insulin secretion) as well as the HOMA-IR (surrogate for evaluation of the degree of insulin resistance) in the remission group. The AA concluded that the improvement of beta-cell function, particularly the restoration of the first-phase insulin secretion, could be responsible for the remission (85). Summary / Conclusions Among the clinical interventions to preserve or “rejuvenate” beta-cells, short term intensive insulin therapy of newly diagnosed DM2 has been proposed: 2-3 weeks intensive therapy with multiple daily insulin injection of NPH+ regular or continuous subcutaneous insulin infusion. The improvement of beta-cell function, especially the restoration of the first phase insulin secretion would lead to remission at least for a period of time. Furthermore, proinsulin decreased highly significantly as did proinsulin-to-insulin- ratio, indicating an improvement in the quality of insulin secretion. B. Modulation of the beta-cell ATP-sensitive K + (K ATP ) channel It has been well demonstrated that insulin release by the beta-cell is initiated by an increase in the intracellular Ca 2+ concentration which is mediated by Ca 2+ influx through voltage-gated Ca 2+ channels in the plasma membrane. The opening and closing (gating) of these Ca 2+ channels is determined by beta-cell membrane potential, which is in turn regulated by the activity of the K ATP channel. In the unstimulated beta cell, K ATP channels are open and the outward movement of K + ions through these channels holds the membrane potential at a hyperpolarized level at which voltage-gated Ca 2+ channels are closed. When plasma glucose concentration rises, glucose uptake and metabolism by the pancreatic beta-cell are enhanced and possibly through changes in intracellular adenine nucleotide concentrations, induces K ATP channel closure. This leads to membrane depolarization, opening voltage-gated Ca 2+ channels and an increase in cytosolic Ca 2+ that
Page 1 and 2: Endocrine Reviews. First published
Page 3 and 4: 3 Sitagliptin (MK-0431) Vildaglipti
Page 5 and 6: 5 associated with impairment of bet
Page 7 and 8: 7 kindreds (but not similar obese c
Page 9 and 10: 9 It is well recognized that the re
Page 11 and 12: 11 Opinions diverge regarding the r
Page 13 and 14: 13 time-dependent establishment of
Page 15 and 16: 15 that plasma FFA support between
Page 17 and 18: 17 generation of reactive oxygen sp
Page 19 and 20: 19 D. Islet-cell amyloid The releva
Page 21 and 22: 21 reduced beta-cell mass can lead
Page 23: 23 Numbering among the factors for
Page 27 and 28: 27 These effects could be dissociat
Page 29 and 30: 29 in in vitro studies in rodent an
Page 31 and 32: 31 suppression of TNF-α expression
Page 33 and 34: 33 Zeender et al. (127) were able t
Page 35 and 36: 35 comparison with both placebo and
Page 37 and 38: 37 Diabetes Prevention Program (DPP
Page 39 and 40: 39 with significant improvement in
Page 41 and 42: 41 mediated by inhibition of glucag
Page 43 and 44: 43 with DM2 (81, 180, 170). Its sub
Page 45 and 46: 45 Table 2. Effects of incretin (GL
Page 47 and 48: 47 Three similarly designed 6-month
Page 49 and 50: 49 function:early (first-phase) ins
Page 51 and 52: 51 whereas the sub-acute effect is
Page 53 and 54: 53 Concerning the potential mediato
Page 55 and 56: 55 in 741 patients with DM2, random
Page 57 and 58: 57 cell function was examined in dr
Page 59 and 60: 59 available to enable comparison o
Page 61 and 62: 61 mathematical model. In a similar
Page 63 and 64: 63 to an excessive glucose producti
Page 65 and 66: 2 14. Weyer C,Bogardus C,Mott DM,Pr
Page 67 and 68: 4 39. Clark A,Wells CA,Buley ID Cru
Page 69 and 70: 6 63. Yaney GC,Corkey BE 2003 Fatty
Page 71 and 72: 8 89. Bell DSH 2004 Management of t
Page 73 and 74: 10 113. Dubois M,Pattou F,Carr-Cont
Page 75 and 76:
12 135. Li J,Tian H,Ren Y,Yu H,Wang
Page 77 and 78:
14 158 Hansen L, Holst JJ 2005 The
Page 79 and 80:
16 183. Farilla L,Hui H,Bertolloto
Page 81 and 82:
18 206. Visboll T,Agerso H,Krarup T
Page 83 and 84:
20 229. Herman GA,Zhao P-L,Dietrich
Page 85:
22 250. Stoffers DA,Kieffer TJ,Huss
show all

1 BETA-CELL FAILURE IN DIABETES AND PRESERVATION BY ...

You also want an ePaper? Increase the reach of your titles

Delete template?

Save as template?