␤-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

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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.

There is an epidemic of obesity worldwide. The prevalence of obesity has doubled over the last three decades. Obesity, especially abdominal obesity is associated with insulin resistance that can lead to pancreatic steatosis and non-alcoholic fatty pancreatic disease (NAFPD). NAFPD describes a phenotype entity ranging from deposition of fat in the pancreas to pancreatic inflammation, and resultant fibrosis, which is similar to that of non-alcoholic fatty liver disease (NAFLD). NAFPD may represent a meaningful manifestation of metabolic syndrome. Pancreatic steatosis can be diagnosed on ultrasound, computed tomography (CT) scan or magnetic resonance imaging (MRI). In addition to a correlation between pancreatic steatosis and metabolic syndrome, pancreatic steatosis may lead to a worse outcome in pancreatitis and may be an etiological factor in pancreatic cancer, but we need further research to examine the associations, pathophysiology, and the impact of pancreatic steatosis and NAFPD on the human health.