A young college student presents tothe health clinic with symptoms of increased

Question

1. A young college student presents tothe health clinic with symptoms of increased urination (polyuria),avid thirst and water drinking (polydipsia), and weight losswithout dieting. Significant in the family history is her fatherdeath at age 42 of what was said to be "acute diabetes." Herfather, sister and a paternal aunt also have diabetes, described asadult onset or type II. Laboratory evaluationreveals increased glucose in blood (hyperglycemia), urine(glucosuria), and urinary ketones. However, Western blotting ofinsulin species shows normal amounts of protein with a highermolecular size then usual. What is the most likelyexplanation?

Explanation / Answer

Most likely a defect in the splice site of the insulinprohormone. The size difference would be the normal insulin + theC-peptide. Decreased affinity for the receptor and increasedhalf-life of the abnormal insulin would give the describedsymptoms.

INSULIN SYNTHESIS ANDSECRETION

Glucagon-like peptide 1 (GLP-1) is a hormone that is encoded inthe proglucagon gene. It is mainly produced in enteroendocrine Lcells of the gut and is secreted into the blood stream when foodcontaining fat, protein hydrolysate, and/or glucose enters theduodenum. Its particular effects on insulin and glucagon secretionhave generated a flurry of research activity over the past 20 yearsculminating in a naturally occurring GLP-1 receptor (GLP-1R)agonist, exendin 4 (Ex-4), now being used to treat type 2 diabetesmellitus (T2DM). GLP-1 engages a specific guaninenucleotide-binding protein (G-protein) coupled receptor (GPCR) thatis present in tissues other than the pancreas (brain, kidney, lung,heart, and major blood vessels). The most widely studied cellactivated by GLP-1 is the insulin-secreting cell where itsdefining action is augmentation of glucose-induced insulinsecretion. Upon GLP-1R activation, adenylyl cyclase (AC) isactivated and cAMP is generated, leading, in turn, tocAMP-dependent activation of second messenger pathways, such as theprotein kinase A (PKA) and Epac pathways. As well as short-termeffects of enhancing glucose-induced insulin secretion, continuousGLP-1R activation also increases insulin synthesis, cellproliferation, and neogenesis. Although these latter effects cannotbe currently monitored in humans, there are substantialimprovements in glucose tolerance and increases in both first phaseand plateau phase insulin secretory responses in T2DM patientstreated with Ex-4. This review will focus on the effects resultingfrom GLP-1R activation in the pancreas.

Keywords: GLP-1 receptor; Exendin 4; Insulin synthesis andsecretion;

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