No abstract

␤-Cell mass can expand in response to demand: during pregnancy, in the setting of insulin resistance, or after pancreatectomy. It is not known whether similar ␤-cell hyperplasia occurs following immune therapy of autoimmune diabetes, but the clinical remission soon after diagnosis and the results of recent immune therapy studies suggest that ␤-cell recovery is possible. We studied changes in ␤-cell replication, mass, and apoptosis in NOD mice during progression to overt diabetes and following immune therapy with anti-CD3 monoclonal antibodies (mAbs) or immune regulatory T-cells (Tregs). ␤-Cell replication increases in pre-diabetic mice, after adoptive transfer of diabetes with increasing islet inflammation but before an increase in blood glucose concentration or a significant decrease in ␤-cell mass. The pathogenic cells are responsible for increasing ␤-cell replication because replication was reduced during diabetes remission induced by anti-CD3 mAb or Tregs. ␤-Cell replication stimulated by the initial inflammatory infiltrate results in increased production of new ␤-cells after immune therapy and increased ␤-cell area, but the majority of this increased ␤-cell area represents regranulated ␤-cells rather than newly produced cells. We conclude that ␤-cell replication is closely linked to the islet inflammatory process. A significant proportion of degranulated ␤-cells remain, at the time of diagnosis of diabetes, that can recover after metabolic correction of hyperglycemia. Correction of the ␤-cell loss in type 1 diabetes will, therefore, require strategies that target both the immunologic and cellular mechanisms that destroy and maintain ␤-cell mass. Diabetes 55:3238 -3245, 2006

Immune modulators can arrest loss of insulin secretion in type 1 diabetes mellitus (T1DM), but they have not caused permanent disease remission or restored normal insulin secretion. We tested whether exendin-4, a glucagon-like peptide-1 receptor agonist, would enhance remission of T1DM in NOD mice treated with anti-CD3 monoclonal antibody (mAb) and studied the effects of exendin-4 treatment on cellular and metabolic responses of beta-cells. Diabetic NOD mice treated with anti-CD3 mAb and exendin-4 had a higher rate of remission (44%) than mice treated with anti-CD3 mAb alone (37%) or exendin-4 (0%) or insulin or IgG alone (0%) (P < 0.01). The effect of exendin-4 on reversal of diabetes after anti-CD3 mAb was greatest in mice with a glucose level of less than 350 mg/dl at diagnosis (63 vs. 39%, P < 0.05). Exendin-4 did not affect beta-cell area, replication, or apoptosis or reduce the frequency of diabetogenic or regulatory T cells or modulate the antigenicity of islet cells. Reversal of T1DM with anti-CD3 mAb was associated with recovery of insulin in glucose transporter-2(+)/insulin(-) islet cells that were identified at diagnosis. Glucose tolerance and insulin responses improved in mice treated with combination therapy, and exendin-4 increased insulin content and insulin release from beta-cells. We conclude that treatment with glucagon-like peptide-1 receptor agonist enhances remission of T1DM in NOD mice treated with anti-CD3 mAb by enhancing the recovery of the residual islets. This combinatorial approach may be useful in treatment of patients with new-onset T1DM.

The antidiabetic activity of Momordica charantia (L.), Cucurbitaceae, a widely-used treatment for diabetes in a number of traditional medicine systems, was investigated in vitro. Antidiabetic activity has been reported for certain saponins isolated from M. charantia. In this study insulin secretion was measured in MIN6 β-cells incubated with an ethanol extract, saponin-rich fraction, and five purified saponins and cucurbitane triterpenoids from M. charantia, 3β,7β,25-trihydroxycucurbita-5,23(E)-dien-19-al (1), momordicine I (2), momordicine II (3), 3-hydroxycucurbita-5,24-dien-19-al-7,23-di-O-β-glucopyranoside (4), and kuguaglycoside G (5). Treatments were compared to incubation with high glucose (27 mM) and the insulin secretagogue, glipizide (50 μM). At 125 μg/ml, an LC-ToF-MS characterized saponin-rich fraction stimulated insulin secretion significantly more than the DMSO vehicle, p=0.02. At concentrations 10 and 25 μg/ml, compounds 3 and 5 also significantly stimulated insulin secretion as compared to the vehicle, p≤0.007, and p= 0.002, respectively. This is the first report of a saponin-rich fraction, and isolated compounds from M. charantia, stimulating insulin secretion in an in vitro, static incubation assay.

Aim of the study-Costus spicatus Sw. (Costaceae) is a prominent medicinal herb used by Dominicans in the Dominican Republic and the United States for the treatment of diabetes, a growing epidemic in the Hispanic community. An ethnobotanical survey of the Dominican community in New York City revealed the popular use of a tea from the insulina plant to treat hyperglycemia. Insulina was identified as Costus spicatus. We tested the ability of a tea made from the leaves of Costus spicatus to alter glucose homeostasis in C57BLKS/J (KS) db/db mice, a model of obesityinduced hyperglycemia with progressive beta cell depletion.Materials and methods-From 6 to 16 weeks of age, Experimental and Control animals (n = 6/5) were given ad lib access to Costus spicatus tea or water, respectively.Results-Weight gain and progression of hyperglycemia and insulinopenia between the Experimental and Control groups were statistically indistinguishable. There was no difference between groups in average fed or fasting glucose and insulin concentrations. Intraperitoneal (IP) insulin tolerance testing after the 10-week study period showed that Costus spicatus tea consumption did not alter insulin sensitivity.Conclusions-These data suggest that at the dose given, tea made from Costus spicatus leaves had no efficacy in the treatment of obesity-induced hyperglycemia. More investigation is needed to more fully explore dosages and the possible utility and biological activity of this common Dominican herbal remedy for the treatment of type 2 diabetes mellitus.