humulin-s and Pancreatic-Neoplasms

A 69-year-old female patient and a 70-year-old male patient were admitted to hospital with recurrent, severe hypoglycemic episodes and a typical manifestation of Whipple's triad. In the female, elevated levels of insulin, C‑peptide and pro-insulin together with pathological findings during a fasting test proved the presence of an insulinoma, which could be detected by Ga-68-DOTATOC-PET-CT in the pancreas. There was a very rare co-existence of a neuroendocrine Merkel cell carcinoma. In the male, levels of insulin and C‑peptide were suppressed and a diagnosis of paraneoplastic hypoglycemia by IGF‑2 secretion was made with increased glucose disposal in skeletal muscle proven by. Eine 69-jährige Patientin und ein 70-jähriger Patient wurden mit rezidivierenden, schweren Hypoglykämien und klinischer Whipple-Trias aufgenommen. Bei der Patientin ließen erhöhte Spiegel an Insulin und C‑Peptid, ein pathologischer insulinogener Index und ein Fastentest an ein Insulinom denken, welches im

Topics: Aged; C-Peptide; Female; Gallium Radioisotopes; Humans; Hypoglycemia; Insulin; Insulin, Regular, Human; Male; Pancreatic Neoplasms; Positron Emission Tomography Computed Tomography

The decreased β-cell mass and impaired β-cell functionality are the primary causes of diabetes mellitus (DM). Nevertheless, the underlying molecular mechanisms by which β-cell growth and function are controlled are not fully understood. In this work, we show that leucettines, known to be DYRK1A kinase inhibitors, can improve glucose-stimulated insulin secretion (GSIS) in rodent β-cells and isolated islets, as well as in hiPSC-derived β-cells islets. We confirm that DYRK1A is expressed in murine insulinoma cells MIN6. In addition, we found that treatment with selected leucettines stimulates proliferation of β-cells and promotes MIN6 cell cycle progression to the G2/M phase. This effect is also confirmed by increased levels of cyclin D1, which is highly responsive to proliferative signals. Among other leucettines, leucettine L43 had a negligible impact on β-cell proliferation, but markedly impair GSIS. However, leucettine L41, in combination with LY364947, a, a potent and selective TGF-β type-I receptor, significantly promotes GSIS in various cellular diabetic models, including MIN6 and INS1E cells in 2D and 3D culture, iPSC-derived β-cell islets derived from iPSC, and isolated mouse islets, by increased insulin secretion and decreased glucagon level. Our findings confirm an important role of DYRK1A inhibitors as modulators of β-cells function and suggested a new potential target for antidiabetic therapy. Moreover, we show in detail that leucettine derivatives represent promising antidiabetic agents and are worth further evaluation, especially in vivo.

Topics: Animals; Glucose; Insulin; Insulin-Secreting Cells; Insulin, Regular, Human; Islets of Langerhans; Mice; Organoids; Pancreatic Neoplasms