Mechanisms of Beta Cell Death in Diabetes: Minor Role for CD95

It has been speculated that beta cell death results from CD95 ligand (CD95L)-induced apoptosis that results from binding of the CD95 ligand to the infiltrating T cells.

Also, studies with perforin-deficient NOD mice indicated that cytotoxic, CD8+ T cell attack is crucial in the final progression to diabetes.

Normal pancreatic islet cells do not express CD95 receptor in humans or mice.  Islet cells can synthesize the receptor in vitro, after incubation with interleukin 1b, or in vivo, after leukocyte infiltration.  Two groups used a CD95-deficient variant (lpr) of the NOD mouse and showed that diabetogenic NOD spleen cells or a NOD-derived CD8+ T cell clone specific for beta cells did not cause diabetes when transferred into NODlpr recipients. They also concluded that induction of CD95 expression on beta cells, and its engagement by CD95L on infiltrating T cells, represented the main pathogenic mechanism in autoimmune diabetes.

The findings of the research in the present study indicate that CD95 has a minor role in the effector phase of the autoimmune response but give no clue as to its involvement in initiation of disease. CD8+ T cells are essential to initiate infiltration in the NOD mouse pancreas, and the studies with perforin-deficient NOD animals have shown that perforin was not required for this to happen. CD95 may be a candidate, but because the immune system of lpr mice is so distorted, it is difficult to conclude anything from these animals, even though they do not develop insulitis.

References:

1.               Allison, J and Strasser, A.  (1998) Proc. Natl. Acad. Sci. USA. 95, 13818 – 13822.

2.               Kagi, D., Odermatt, B., Seiler, P., Zinkernagel, R. M., Mak, T. W. & Hengartner, H. (1997) J. Exp. Med. 186, 989–997.

3.               Nagata, S. (1997) Cell 88, 355–365.

4.               Stassi, G., Todaro, M., Richiusa, P., Giordano, M., Mattina, A., Sbriglia, M. S., Lo Monte, A., Buscemi, G., Galluzzo, A. & Giordano, C. (1995) Tranplant. Proc. 27, 3271–3275.

5.               Yamada, K., Takane-Gyotoku, N., Yuan, X., Ichikawa, F., Inada, C. & Nonaka, K. (1996) Diabetologia 39, 1306–1312.

6.               Itoh, N., Imagawa, A., Hanafusa, T., Waguri, M., Yamamoto, K., Iwahashi, H., Moriwaki, M., Nakajima, H., Miyagawa, J., Namba, M., et al. (1997) J. Exp. Med. 186, 613–618.

Is Type 1 Diabetes Transmissible by Bone Marrow Allograft?

A review published in the Lancet in 1993 suggested that type 1 diabetes in a bone marrow allograft donor might be transmitted to the recipient after a successful transplant. A 21- year follow-up report of this study after a successful allograft for aplastic anemia indicated that the recipient had developed a number of antibodies against pancreatic islet cells, and although these persisted for a number of years, she did not develop diabetes. The donor had type 1-diabetes at the time of transplant. 

In a bone marrow transplant that occurred in 1979, the donor had been diagnosed with type 1 diabetes seven years prior to transplantation, and was negative for islet cell antibodies (ICAs).  Overtime, the recipient developed ICAs and high levels of anti-GAD (glutamic acid decarboxylase) antibodies.  The patient also had chronic GVHD (Graft versus host disease), a condition in which multiple autoantibodies are commonly found.  The presence of ICAs and anti-GAD antibodies might not be related to the fact that the donor had type 1 diabetes. Alternatively, the autoimmune process observed in the recipient may have been modified by the Azathioprine therapy, which was in place for 6 years immediately post-transplant.  Blood glucose measurements over the past 21 years have shown no evidence of type 1 diabetes.

References:

1. Lampeter EF, Homberg M, Quabeck K, Schaefer UW, Werner P, Bertrams J, Grosse- Wilde H, Gries FA, Kolb H: Transfer of insulin-dependent diabetes between HLA- identical siblings by bone marrow trans- plantation. Lancet 341:1243–1244, 1993.

 2. Lampeter EF, McCann SR, Kolb H: Transfer of insulin-dependent diabetes by bone marrow transplantation. Lancet 351:568 – 569, 1998.

3. Kulmala P, Savola K, Reijonen H, Veijola R, Vahasalo P, Karjalainen J, Tuom- ilehto-Wolf E, Ilonen J, Tuomilehto J, Akerblom HK, Knip M, the Childhood Diabetes in Finland Study Group: Genetic markers, humoral autoimmunity, and prediction of type 1 diabetes in sib- lings of affected children. Diabetes 49: 48 –58, 2000.

4. Quaranta S, Shulman H, Ahmed A, Shoenfeld Y, Peter J, McDonald GB, Van de Water J, Coppel R, Ostlund C, Worman HJ, Rizzetto M, Tsuneyama K, Na- kanuma Y, Ansari A, Locatelli F, Paganin S, Rosina F, Manns M, Gershwin ME: Autoantibodies in human chronic graft- versus-host disease after hematopoietic cell transplantation. Clinical Immunology 91:106 –116, 1999.

Beneficial Effect of Diabetes on Acute Intermittent Porphyria

Acute Intermittent Porphyria (AIP) is an autosomal hereditary metabolic aberration resulting from a partial defect in the activity of the third-step enzyme (porphobilinogen deaminase [PBGD]) during the course of heme synthesis.  Carbohydrate ingestion blocks the enzyme d-aminolevulinic acid (ALA)- synthase.  The mechanisms by which carbohydrates modulate the components of porphyrins and heme synthesis are highly complex and only partially elucidated to date.

Long-term complications of AIP are polyneuropathy, hepatocellular carcinoma (HCC), and renal insufficiency. Treatment of AIP patients entails treating both the symptoms and the complications, but also requires an endeavor to reverse the fundamental disease by prescribing a carbohydrate-rich diet and by treating the attacks with intravenous infusions of glucose or heme.

In a study conducted in northern Sweden included a total of 16 patients (5 women) with AIP and type 2-diabetes with a mean age of 67 years. Eight of these patients had AIP symptoms, with three patients suffering severe, recurring attacks. After the onset of their diabetes, no patient suffered attacks or any other AIP symptoms.  Recurrent AIP attacks ceased when the patients became diabetic. None of the 16 diabetic patients with AIP had HCC. In another study, of all the 30 AIP patients with HCC registered, none had diabetes, whereas in a population-based group of individuals in southern Sweden (mean age 67 years), diabetes was found in 12.8% of the men and 15.0% of the women. This suggests that diabetes also counteracts HCC in AIP patients, probably by normalization of ALA.

References:

1.         Strand LJ, Meyer UA, Felsher BF, Redeker AC, Marver HS: Decreased red cell uro- porphyrinogen 1 synthetase activity in in- termittent acute porphyria. J Clin Invest 51:2530 –2536, 1972.

2.         Doss M, Verspohl F: The “glucose effect” in acute hepatiac porphyrias and in exper- imental porphyria. Klin Wschr 9:727– 735,1981.

3.         Wikberg A, Andersson C, Lithner F: Signs of neuropathy in the lower legs and feet of patients with acute intermittent porphy- ria. J Intern Med 248:27–32, 2000.

4.         Andersson C, Bjersing L, Lithner F: The epidemiology of hepatocellular carci- noma in patients with acute intermittent porphyria. J Intern Med 240:195–201, 1996.

5.         Andersson C, Wikberg A, Stegmayr B, Lithner F: Renal symptomatology in pa- tients with acute intermittent porphyria: a population-based study. J Intern Med 248: 319 –325, 2000.

6.         Mustajoki P, Normann Y: Early administra- tion of heme arginate for acute porphyric attacks. Arch Intern Med 153:2004 –2008, 1993

Role of SIRT1 Mutation in Onset of Type 1 Diabetes

Type 1 diabetes, caused by autoimmune-mediated β cell destruction, leads to insulin deficiency.  The histone deacetylase SIRT1 is prominently expressed in β cells and regulates insulin secretion².  SIRT1 plays a critical role in modulating several age-related diseases.  An article published in the journal Cell Metabolism describes a family carrying a mutation in the SIRT1 gene.  All five affected members developed an autoimmune disorder: four developed type 1 diabetes, and one developed ulcerative colitis.  Direct and exome sequencing identified the presence of a T-to-C exchange in exon 1 of SIRT1, corresponding to a leucine-to-proline mutation at residue 107. Expression of SIRT1-L107P in insulin-producing cells resulted in overproduction of nitric oxide, cytokines, and chemokines.  These observations identify a role for SIRT1 in human autoimmunity and unveil a monogenic form of type 1 diabetes.

Reference:

1.                  Biason-Lauber, et.al.  “Identification of a SIRT1 Mutation in a Family With Type 1 Diabetes.”  Cell Metabolism 17.  Supplement 3 (2013): 448 - 455.

2.                  Bordone, et al.  “SIRT1 Regulates Insulin Secretion by Expressing UCP2 in Pancreatic Beta Cells.”  PLoS Biology 4.  Supplement 2 (2006): e31.

Treatment of Diabetes and Long-Term Survival After Insulin and Glucokinase Gene Therapy

This paper explores the idea of long-term correction of diabetes in a large animal model using gene transfer.  Previous research by Mas et al., demonstrated that it is possible to generate a “glucose sensor” in skeletal muscle through coexpression of glucokinase and insulin, increasing glucose uptake and correcting hyperglycemia in diabetic mice.  This study was conducted in larger animals using viral vectors.  A one-time intramuscular administration of adeno-associated viral vectors of serotype 1 encoding for glucokinase and insulin in diabetic dogs resulted in normalization of fasting glycemia, accelerated disposal of glucose after oral challenge.  There were no episodes of hypoglycemia during exercise for more than 4 years after gene transfer.  No secondary compications were observed in these animal models.In contrast, exogenous insulin or gene transfer for insulin or glucokinase alone failed to achieve complete correction of diabetes, indicating that the synergistic action of insulin and glucokinase is needed for full therapeutic effect. This study provides the first proof-of-concept in a large animal model for a gene transfer approach to treat diabetes (Fig 1).