MEDICAL HYPOTHESES AND RESEARCH
VOL. 2, No. 2, January 2005



H. Kaneto [2005] Med Hypotheses Res 2: 379-391.


Possible Molecular Mechanism for Glucose Toxicity in
Type 2 Diabetes


Hideaki Kaneto*

Department of Internal Medicine and Therapeutics, Osaka University Graduate School of
Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan


Abstract.  The hallmark of Type 2 diabetes is pancreatic β-cell dysfunction and insulin
resistance. Normal β-cells can compensate for insulin resistance by increasing insulin
secretion and/or β-cell mass, but insufficient compensation leads to the onset of glucose
intolerance. Once hyperglycemia becomes apparent, β-cell function gradually deteriorates
and insulin resistance aggravates. This process is called “glucose toxicity”. Under diabetic
conditions, oxidative stress and ER stress are induced in various tissues, both of which are
involved in the glucose toxicity. Induction of oxidative stress and/or ER stress leads to
activation of the JNK pathway, which suppresses insulin biosynthesis and interferes with
insulin signaling. In contrast, suppression of the JNK pathway in diabetic mice improves
insulin resistance and ameliorates glucose tolerance. We assume that such phenomena can
explain, at least in part, the molecular mechanism for glucose toxicity found in Type 2
diabetes.



*Address all correspondence to: Dr. Hideaki Kaneto, Department of Internal Medicine and
Therapeutics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka
565-0871, Japan.  Phone: 81-6-6879-3633. Fax: 81-6-6879-3639.
E-Mail:
kaneto@medone.med.osaka-u.ac.jp



Full Text [PDF]