Browsing by Author "Bahnson, Henry T."

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    Abnormalities in proinsulin processing in islets from individuals with longstanding T1D
    (Elsevier, 2019-11) Sims, Emily K.; Syed, Farooq; Nyalwidhe, Julius; Bahnson, Henry T.; Haataja, Leena; Speake, Cate; Morris, Margaret A.; Balamurugan, Appakalai N.; Mirmira, Raghavendra G.; Nadler, Jerry; Mastracci, Teresa L.; Arvan, Peter; Greenbaum, Carla J.; Evans-Molina, Carmella; Pediatrics, School of Medicine
    We recently described the persistence of detectable serum proinsulin in a large majority of individuals with longstanding type 1 diabetes (T1D), including individuals with undetectable serum C-peptide. Here, we sought to further explore the mechanistic etiologies of persistent proinsulin secretion in T1D at the level of the islet, using tissues obtained from human donors. Immunostaining for proinsulin and insulin was performed on human pancreatic sections from the Network for Pancreatic Organ Donors with Diabetes (nPOD) collection (n = 24). Differential proinsulin processing enzyme expression was analyzed using mass spectrometry analysis of human islets isolated from pancreatic sections with laser capture microdissection (n = 6). Proinsulin processing enzyme mRNA levels were assessed using quantitative real-time PCR in isolated human islets (n = 10) treated with or without inflammatory cytokines. Compared to nondiabetic controls, immunostaining among a subset (4/9) of insulin positive T1D donor islets revealed increased numbers of cells with proinsulin-enriched, insulin-poor staining. T1D donor islets also exhibited increased proinsulin fluorescence intensity relative to insulin fluorescence intensity. Laser capture microdissection followed by mass spectrometry revealed reductions in the proinsulin processing enzymes prohormone convertase 1/3 (PC1/3) and carboxypeptidase E (CPE) in T1D donors. Twenty-four hour treatment of human islets with inflammatory cytokines reduced mRNA expression of the processing enzymes PC1/3, PC2, and CPE. Taken together, these data provide new mechanistic insight into altered proinsulin processing in long-duration T1D and suggest that reduced β cell prohormone processing is associated with proinflammatory cytokine-induced reductions in proinsulin processing enzyme expression.
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    High residual C-peptide likely contributes to glycemic control in type 1 diabetes
    (American Society for Clinical Investigation, 2020-01-02) Rickels, Michael R.; Evans-Molina, Carmella; Bahnson, Henry T.; Ylescupidez, Alyssa; Nadeau, Kristen J.; Hao, Wei; Clements, Mark A.; Sherr, Jennifer L.; Pratley, Richard E.; Hannon, Tamara S.; Shah, Viral N.; Miller, Kellee M.; Greenbaum, Carla J.; Medicine, School of Medicine
    BACKGROUND Residual C-peptide is detected in many people for years following the diagnosis of type 1 diabetes; however, the physiologic significance of low levels of detectable C-peptide is not known. METHODS We studied 63 adults with type 1 diabetes classified by peak mixed-meal tolerance test (MMTT) C-peptide as negative (<0.007 pmol/mL; n = 15), low (0.017–0.200; n = 16), intermediate (>0.200–0.400; n = 15), or high (>0.400; n = 17). We compared the groups’ glycemia from continuous glucose monitoring (CGM), β cell secretory responses from a glucose-potentiated arginine (GPA) test, insulin sensitivity from a hyperinsulinemic-euglycemic (EU) clamp, and glucose counterregulatory responses from a subsequent hypoglycemic (HYPO) clamp. RESULTS Low and intermediate MMTT C-peptide groups did not exhibit β cell secretory responses to hyperglycemia, whereas the high C-peptide group showed increases in both C-peptide and proinsulin (P ≤ 0.01). All groups with detectable MMTT C-peptide demonstrated acute C-peptide and proinsulin responses to arginine that were positively correlated with peak MMTT C-peptide (P < 0.0001 for both analytes). During the EU-HYPO clamp, C-peptide levels were proportionately suppressed in the low, intermediate, and high C-peptide compared with the negative group (P ≤ 0.0001), whereas glucagon increased from EU to HYPO only in the high C-peptide group compared with negative (P = 0.01). CGM demonstrated lower mean glucose and more time in range for the high C-peptide group. CONCLUSION These results indicate that in adults with type 1 diabetes, β cell responsiveness to hyperglycemia and α cell responsiveness to hypoglycemia are observed only at high levels of residual C-peptide that likely contribute to glycemic control. FUNDING Funding for this work was provided by the Leona M. and Harry B. Helmsley Charitable Trust, the National Center for Advancing Translational Sciences, and the National Institute of Diabetes and Digestive and Kidney Diseases.
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    Proinsulin Secretion Is a Persistent Feature of Type 1 Diabetes
    (American Diabetes Association, 2019-02) Sims, Emily K.; Bahnson, Henry T.; Nyalwidhe, Julius; Haataja, Leena; Davis, Asa K.; Speake, Cate; DiMeglio, Linda A.; Blum, Janice; Morris, Margaret A.; Mirmira, Raghavendra G.; Nadler, Jerry; Mastracci, Teresa L.; Marcovina, Santica; Qian, Wei-Jun; Yi, Lian; Swensen, Adam C.; Yip-Schneider, Michele; Schmidt, C. Max; Considine, Robert V.; Arvan, Peter; Greenbaum, Carla J.; Evans-Molina, Carmella; T1D Exchange Residual C-peptide Study Group; Pediatrics, School of Medicine
    OBJECTIVE: Abnormally elevated proinsulin secretion has been reported in type 2 and early type 1 diabetes when significant C-peptide is present. We questioned whether individuals with long-standing type 1 diabetes and low or absent C-peptide secretory capacity retained the ability to make proinsulin. RESEARCH DESIGN AND METHODS: C-peptide and proinsulin were measured in fasting and stimulated sera from 319 subjects with long-standing type 1 diabetes (≥3 years) and 12 control subjects without diabetes. We considered three categories of stimulated C-peptide: 1) C-peptide positive, with high stimulated values ≥0.2 nmol/L; 2) C-peptide positive, with low stimulated values ≥0.017 but <0.2 nmol/L; and 3) C-peptide <0.017 nmol/L. Longitudinal samples were analyzed from C-peptide-positive subjects with diabetes after 1, 2, and 4 years. RESULTS: Of individuals with long-standing type 1 diabetes, 95.9% had detectable serum proinsulin (>3.1 pmol/L), while 89.9% of participants with stimulated C-peptide values below the limit of detection (<0.017 nmol/L; n = 99) had measurable proinsulin. Proinsulin levels remained stable over 4 years of follow-up, while C-peptide decreased slowly during longitudinal analysis. Correlations between proinsulin with C-peptide and mixed-meal stimulation of proinsulin were found only in subjects with high stimulated C-peptide values (≥0.2 nmol/L). Specifically, increases in proinsulin with mixed-meal stimulation were present only in the group with high stimulated C-peptide values, with no increases observed among subjects with low or undetectable (<0.017 nmol/L) residual C-peptide. CONCLUSIONS: In individuals with long-duration type 1 diabetes, the ability to secrete proinsulin persists, even in those with undetectable serum C-peptide.
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    Response to Comment on Sims et al. Proinsulin Secretion Is a Persistent Feature of Type 1 Diabetes. Diabetes Care 2019;42:258–264
    (American Diabetes Association, 2019-05) Sims, Emily K.; Bahnson, Henry T.; Nyalwidhe, Julius; Haataja, Leena; Davis, Asa K.; Speake, Cate; DiMeglio, Linda A.; Blum, Janice; Morris, Margaret A.; Mirmira, Raghavendra G.; Nadler, Jerry; Mastracci, Teresa L.; Marcovina, Santica; Qian, Wei-Jun; Yi, Lian; Swensen, Adam C.; Yip-Schneider, Michele; Schmidt, C. Max; Considine, Robert V.; Arvan, Peter; Greenbaum, Carla J.; Evans-Molina, Carmella; Pediatrics, School of Medicine