Original Data
| Rev Diabet Stud,
2004,
1(2):66-79 |
DOI 10.1900/RDS.2004.1.66 |
Enriched Human Pancreatic Ductal Cultures Obtained from Selective Death of Acinar Cells Express Pancreatic and Duodenal Homeobox Gene-1 Age-Dependently
Cale N. Street1, Jonathan R.T. Lakey1,2, Ray V. Rajotte1,2, A.M. James Shapiro1,2, Timothy J. Kieffer3,4, James G. Lyon1, Tatsuya Kin1, Gregory S. Korbutt1,2,4
1Surgical Medical Research Institute, University of Alberta, Edmonton, AB, Canada T6G 2N8.
2Department of Surgery, University of Alberta, Edmonton, AB, Canada T6G 2R3.
3Department of Physiology, University of Alberta, Edmonton, AB, Canada T6G 2R3.
4Stem Cell Network of Canada, University of Alberta, Edmonton, AB, Canada T6G 2R3.
Address correspondence to: Gregory S. Korbutt, e-mail: korbutt@ualberta.ca
Abstract
Adult pancreatic ductal cells are believed to be islet precursors. Our aim was to obtain an enriched human ductal cell population in defined culture conditions, and to characterize these cultures for the presence of pancreatic developmental transcription factors. Non-endocrine adult human pancreatic digest was cultured for 4 days in serum-containing and serum-free media. During this time, analysis was done for phenotypic changes, cell death, and expression of islet and islet precursor markers. Culture in serum-supplemented and serum-free media gave similar recoveries of an enriched ductal population after 4 days. Extensive cell death due to apoptosis and necrosis was also observed over this time period. A donor-age dependent expression of pancreatic and duodenal homeobox gene-1 (PDX-1) in ductal cells was seen at 4 days whereby donors <25 yr expressed significantly more than donors >25 yr. Analysis of gene expression by RT-PCR showed the presence of islet developmental transcription factors neuroD, Nkx6.1, and PDX-1, as well as mature islet hormones. While acinar-ductal transdifferentiation of some cells cannot be ruled out, we provide evidence that the predominant mechanism for the derivation of enriched human ductal cultures in our culture conditions is selective acinar cell death. Furthermore, we have shown that ductal cultures from younger donors exhibit greater plasticity through expression of PDX-1, and may be of greater value in attempts to induce islet neogenesis. The presence, however, of insulin and glucagon mRNA indicates that contaminating endocrine cells remain in these cultures and underscores the need to use caution when assessing differentiation potential.
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| Rev Diabet Stud,
2004,
1(2):80-88 |
DOI 10.1900/RDS.2004.1.80 |
Polyclonal Anti-T-Cell Therapy for Type 1 Diabetes Mellitus of Recent Onset
Frantisek Saudek, Tereza Havrdova, Petr Boucek, Ludmila Karasova, Peter Novota, Jelena Skibova
Diabetes Center, Institute for Clinical and Experimental Medicine, Videnska 1958/9, 14021 Prague 4, Czech Republic.
Address correspondence to: Frantisek Saudek, e-mail: frantisek.saudek@medicon.cz
Abstract
The destruction of pancreatic β-cells in type 1 diabetes mellitus is mediated by autoreactive T-lymphocyte clones. We initiated a prospective randomized controlled trial of polyclonal rabbit anti-T-cell globulin (ATG) in patients with type 1 diabetes within 4 weeks of diagnosis and with residual post-glucagon C-peptide levels still over 0.3 nmol/l. ATG was administered as an initial bolus of 9 mg/kg followed by 3 consecutive doses of 3 mg/kg. An interim analysis was performed to establish whether any significant changes in C-peptide production and insulin requirement had occurred that would justify the continuation of this pilot study. By May 2004, 11 subjects were assigned to treatment with ATG along with intensified insulin therapy and 6 to intensified insulin therapy with placebo, and were followed for a period of at least 6 months. During the first 12 months a significant difference in the insulin dose trends was found between the groups (p = 0.010) with a lower insulin dosage in the ATG group. There was also a difference in the glucagon stimulated C-peptide level trends of marginal significance (p = 0.068). Compared to values at screening, stimulated C-peptide levels significantly improved in the ATG group (p = 0.012) but not in the placebo group. Complete diabetes remission occurred in 2 patients in the ATG and in none of the placebo group. Glycosylated hemoglobin at 12 months tended to be lower in the ATG group (p = 0.088). Significant adverse effects of ATG treatment, mainly transient fever and moderate symptoms of serum sickness (7 and 6 subjects, respectively) were observed during the first month only. The interim analysis of this ongoing study suggests that short-term ATG therapy in type 1 diabetes of recent onset contributes to the preservation of residual C-peptide production and to lower insulin requirements in the first year following diagnosis.
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| Rev Diabet Stud,
2004,
1(2):89-94 |
DOI 10.1900/RDS.2004.1.89 |
"Low Dose" Metformin Improves Hyperglycemia Better Than Acarbose in Type 2 Diabetics
Ken Yajima1,2, Akira Shimada1, Hiroshi Hirose1, Akira Kasuga3, Takao Saruta1
1Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
2Department of Internal Medicine, Hamamatsu Red Cross Hospital, Hamamatsu, 430-0907, Japan.
3Department of Internal Medicine, Tokyo Denryoku Hospital, Tokyo, 160-0016, Japan.
Address correspondence to: Akira Shimada, e-mail: asmd@st.itc.keio.ac.jp
Abstract
OBJECTIVES: "High dose" metformin therapy (2,550 mg/day) is reported to improve glycemic control in type 2 diabetic patients with obesity (body mass index (BMI) ≥ 30). Some have reported that metformin therapy, even in low doses (500-750 mg/day), improves glycemic control in non-obese type 2 diabetic patients (BMI approximately 25). However, it is unclear whether "low dose" metformin improves glycemic control better than acarbose in non-obese type 2 diabetic patients, which has been shown to improve glycemic control in type 2 diabetes with obesity. METHODS: We randomly divided 22 non-obese type 2 diabetic patients (mean BMI approximately 25) into two groups (A = 11, B = 11). Group A was treated with "low dose" metformin (500-750 mg/day) for 3 months, and switched to acarbose (150-300 mg/day) for another 3 months. Group B was treated with acarbose first, and then switched to "low dose" metformin. RESULTS: "Low dose" metformin significantly decreased the fasting plasma glucose (FPG) and HbA1c level in both groups A and B, whereas acarbose decreased HbA1c levels in group B but not in group A. Overall, "low dose" metformin significantly decreased HbA1c (p=0.0165) levels as compared to acarbose. CONCLUSION: In conclusion, "low dose" metformin therapy improved glycemic control better than acarbose in non-obese diabetics.
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