title: Synergy Between Gαz Deficiency and GLP-1 Analog Treatment in Preserving Functional β-Cell Mass in Experimental Diabetes.
abstract: A defining characteristic of type 1 diabetes mellitus (T1DM) pathophysiology is pancreatic β-cell death and dysfunction, resulting in insufficient insulin secretion to properly control blood glucose levels. Treatments that promote β-cell replication and survival, thus reversing the loss of β-cell mass, while also preserving β-cell function, could lead to a real cure for T1DM. The α-subunit of the heterotrimeric Gz protein, Gαz, is a tonic negative regulator of adenylate cyclase and downstream cAMP production. cAMP is one of a few identified signaling molecules that can simultaneously have a positive impact on pancreatic islet β-cell proliferation, survival, and function. The purpose of our study was to determine whether mice lacking Gαz might be protected, at least partially, from β-cell loss and dysfunction after streptozotocin treatment. We also aimed to determine whether Gαz might act in concert with an activator of the cAMP-stimulatory glucagon-like peptide 1 receptor, exendin-4 (Ex4). Without Ex4 treatment, Gαz-null mice still developed hyperglycemia, albeit delayed. The same finding held true for wild-type mice treated with Ex4. With Ex4 treatment, Gαz-null mice were protected from developing severe hyperglycemia. Immunohistological studies performed on pancreas sections and in vitro apoptosis, cytotoxicity, and survival assays demonstrated a clear effect of Gαz signaling on pancreatic β-cell replication and death; β-cell function was also improved in Gαz-null islets. These data support our hypothesis that a combination of therapies targeting both stimulatory and inhibitory pathways will be more effective than either alone at protecting, preserving, and possibly regenerating β-cell mass and function in T1DM.
authors.affiliation: Department of Medicine (A.L.B., J.A.W., M.T.C., M.F.T., H.K.B., R.L.P., M.E.K.), Division of Endocrinology, Diabetes, and Metabolism; Department of Cell and Regenerative Biology (M.E.K.); and Interdisciplinary Graduate Program in Nutritional Sciences (R.J.F., M.D.S., M.E.K.), University of Wisconsin-Madison, Madison; and Research Service (A.L.B., J.A.W., M.T.C., M.F.T., R.J.F., H.K.B., M.D.S., M.E.K.), William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin 53705.
authors.forename: Allison L
authors.initials: AL
authors.lastname: Brill
authors.affiliation: Department of Medicine (A.L.B., J.A.W., M.T.C., M.F.T., H.K.B., R.L.P., M.E.K.), Division of Endocrinology, Diabetes, and Metabolism; Department of Cell and Regenerative Biology (M.E.K.); and Interdisciplinary Graduate Program in Nutritional Sciences (R.J.F., M.D.S., M.E.K.), University of Wisconsin-Madison, Madison; and Research Service (A.L.B., J.A.W., M.T.C., M.F.T., R.J.F., H.K.B., M.D.S., M.E.K.), William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin 53705.
authors.forename: Jaclyn A
authors.initials: JA
authors.lastname: Wisinski
authors.affiliation: Department of Medicine (A.L.B., J.A.W., M.T.C., M.F.T., H.K.B., R.L.P., M.E.K.), Division of Endocrinology, Diabetes, and Metabolism; Department of Cell and Regenerative Biology (M.E.K.); and Interdisciplinary Graduate Program in Nutritional Sciences (R.J.F., M.D.S., M.E.K.), University of Wisconsin-Madison, Madison; and Research Service (A.L.B., J.A.W., M.T.C., M.F.T., R.J.F., H.K.B., M.D.S., M.E.K.), William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin 53705.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Cadena
authors.affiliation: Department of Medicine (A.L.B., J.A.W., M.T.C., M.F.T., H.K.B., R.L.P., M.E.K.), Division of Endocrinology, Diabetes, and Metabolism; Department of Cell and Regenerative Biology (M.E.K.); and Interdisciplinary Graduate Program in Nutritional Sciences (R.J.F., M.D.S., M.E.K.), University of Wisconsin-Madison, Madison; and Research Service (A.L.B., J.A.W., M.T.C., M.F.T., R.J.F., H.K.B., M.D.S., M.E.K.), William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin 53705.
authors.forename: Mary F
authors.initials: MF
authors.lastname: Thompson
authors.affiliation: Department of Medicine (A.L.B., J.A.W., M.T.C., M.F.T., H.K.B., R.L.P., M.E.K.), Division of Endocrinology, Diabetes, and Metabolism; Department of Cell and Regenerative Biology (M.E.K.); and Interdisciplinary Graduate Program in Nutritional Sciences (R.J.F., M.D.S., M.E.K.), University of Wisconsin-Madison, Madison; and Research Service (A.L.B., J.A.W., M.T.C., M.F.T., R.J.F., H.K.B., M.D.S., M.E.K.), William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin 53705.
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Fenske
authors.affiliation: Department of Medicine (A.L.B., J.A.W., M.T.C., M.F.T., H.K.B., R.L.P., M.E.K.), Division of Endocrinology, Diabetes, and Metabolism; Department of Cell and Regenerative Biology (M.E.K.); and Interdisciplinary Graduate Program in Nutritional Sciences (R.J.F., M.D.S., M.E.K.), University of Wisconsin-Madison, Madison; and Research Service (A.L.B., J.A.W., M.T.C., M.F.T., R.J.F., H.K.B., M.D.S., M.E.K.), William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin 53705.
authors.forename: Harpreet K
authors.initials: HK
authors.lastname: Brar
authors.affiliation: Department of Medicine (A.L.B., J.A.W., M.T.C., M.F.T., H.K.B., R.L.P., M.E.K.), Division of Endocrinology, Diabetes, and Metabolism; Department of Cell and Regenerative Biology (M.E.K.); and Interdisciplinary Graduate Program in Nutritional Sciences (R.J.F., M.D.S., M.E.K.), University of Wisconsin-Madison, Madison; and Research Service (A.L.B., J.A.W., M.T.C., M.F.T., R.J.F., H.K.B., M.D.S., M.E.K.), William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin 53705.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Schaid
authors.affiliation: Department of Medicine (A.L.B., J.A.W., M.T.C., M.F.T., H.K.B., R.L.P., M.E.K.), Division of Endocrinology, Diabetes, and Metabolism; Department of Cell and Regenerative Biology (M.E.K.); and Interdisciplinary Graduate Program in Nutritional Sciences (R.J.F., M.D.S., M.E.K.), University of Wisconsin-Madison, Madison; and Research Service (A.L.B., J.A.W., M.T.C., M.F.T., R.J.F., H.K.B., M.D.S., M.E.K.), William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin 53705.
authors.forename: Renee L
authors.initials: RL
authors.lastname: Pasker
authors.affiliation: Department of Medicine (A.L.B., J.A.W., M.T.C., M.F.T., H.K.B., R.L.P., M.E.K.), Division of Endocrinology, Diabetes, and Metabolism; Department of Cell and Regenerative Biology (M.E.K.); and Interdisciplinary Graduate Program in Nutritional Sciences (R.J.F., M.D.S., M.E.K.), University of Wisconsin-Madison, Madison; and Research Service (A.L.B., J.A.W., M.T.C., M.F.T., R.J.F., H.K.B., M.D.S., M.E.K.), William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin 53705.
authors.forename: Michelle E
authors.initials: ME
authors.lastname: Kimple
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000139:chemically induced / Q000378:metabolism; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006943:Hyperglycemia / Q000188:drug therapy / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013311:Streptozocin / Q000494:pharmacology; D014688:Venoms / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D010455:Peptides; D014688:Venoms; D013311:Streptozocin; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide; D000262:Adenylyl Cyclases; D005947:Glucose