Anti-diabetes+Drug+Metformin+and+its+Use+as+a+Potential+Pancreatic+Cancer+Treatment

__** Research Question **__ The goal of this project is to investigate the link between diabetes mellitus and developing pancreatic cancer, or more specifically, pancreatic ductal adenocarcinoma (PDAC). We are particularly interested in the anti-diabetic drug metformin which has been known to prevent the progression of pancreatic cancer in various ways (Ref. 1). The two targets of this drug are cancer stem cells, which enable the unrestricted growth characteristic of cancer, and mTOR signaling, a cell growth pathway, to be activated or inactivated under specific conditions (Ref. 2).

__** Introduction **__

__Diabetes Mellitus__

__Pancreatic Cancer__

__The Mitochondrion__ (Complex 1)

__What is Metformin?__ Metformin is sold under the prescription names Glumetza, Fortamet, Riomet, and Glucophage. The difference between the drugs is their delivery (oral solution or slow/fast release tablets). It is prescribed to type 2 diabetic patients to help lower blood glucose levels as a main form of treatment along with diet and exercise (4). People should not take metformin if they have kidney problems, are type 1 diabetic, or have a condition called metabolic acidosis or diabetic ketoacidosis (increased ketones in your blood or urine)(4). Metformin helps the body become more sensitive to its own insulin, decreases the amount of sugar the liver makes, and decreases the amount of sugar the intestine absorbs. (4) (6) Mechanisms:

__** Specifics **__ (change this title later?)

__Understanding the AMP Kinase Signaling Pathway:__ The AMP Kinase is activated under conditions such as low glucose levels and hypoxia that put stress on cells by depleting the cellular ATP (7). When active AMPK positively regulates signaling pathways that bring ATP levels back to homeostatic levels by inducing fatty acid oxidation and autophagy. When active this pathway turns off ATP-consuming biosynthetic processes including gluconeogenesis and synthesis of lipids and proteins.This happens by AMPK phosphorylating enzymes that are involved in the gluconeogenesis process as well as through transcriptional control of metabolism by activating transcription factors, co-activators and co-repressors (7). Additionally, when cAMP concentrations are high it will activate PKA which turns on LKB1 which activates AMPK (7). When ATP levels are low and a AMPK is active it increases TSC2 transcription which is an inhibitor of mTOR(8).

__Understanding the mTOR Signaling Pathway:__ When active, mTOR activates transcription factors that lead to mitochondrial metabolism and adipogenesis and also suppressed autophagy(8). Downstream of mTOR is Akt which is important in promoting cellular survival. Increased mTOR signaling can lead to cancer and metabolic disorders. It is suppressed by TSC2 which is turned on by the active AMP Kinase(8).

PanIN

__Mechanisms in Cancer__

Breast Cancer

Pancreatic Cancer