Inheritance Of Diabetes Mellitus Research Articles

Abstract 038: Hyperglycemia Mediated Cardiac Damage in High-Fat Fed E487K Aldehyde Dehydrogenase 2 (ALDH 2*2) Mutant Diabetic Mice: Role for ALDH2 Activation

Aldehyde dehydrogenase 2 (ALDH2), a mitochondrial enzyme in the heart, detoxifies reactive aldehydes and protects heart from oxidative stress. East Asians (~700 million) are carriers of E487K point mutation of ALDH2 (ALDH2*2) with intrinsically low ALDH2 activity. ALDH2*2 is associated with increased maternal inheritance of diabetes mellitus (DM), and DM-induced neuropathy and vasculopathy. However the pathophysiology of diabetic cardiac damage.is not studied in ALDH2*2 carriers. DM is a polygenic disease and DM-induced cardiac damage may be multifactorial. However we hypothesis that hyperglycemia-induced oxidative stress mediated 4-hydroxy-2-nonel (4HNE) toxicity contributes to the cardiac damage in ALDH2*2 mutant mice (low intrinsic ALDH2 activity) with type-2 diabetes. We induced type-2 diabetes by feeding high-fat diet and found they developed hyperglycemia (blood glucose (BG) levels increased to 357 ± 100 mg/dl vs 137 ± 7 mg/dl) and insulin resistance as measured by glucose tolerance test (GTT) (BG levels 408 ± 50 mg/dl vs 165 ± 18 mg/dl at 2 hours after GTT). To delineate the role of hyperglycemia, we treated the diabetic mice with a sodium-glucose co-transporter 2 (SGLT2) inhibitor, Empaglifuzin (EMP) (3mg/kg/day) or Vehicle for 8 weeks. EMP reduced BG levels from 502 ± 75 mg/dl to 193 ± 50 mg/dl by enhancing urinary glucose excretion. Surprisingly EMP reversed insulin resistance as maintained similar BG levels before and after 2 hours of GTT; 190 ± 23 mg/dl vs 188 ± 16 mg/dl. EMP also increased ALDH2 activity to 22 ± 8 % from 7 ± 3 % and 4HNE protein adduct levels. Finally EMP improved cardiac function i.e. % fractional shortening (FS) is increased to 70 ± 4 compared to 53 ± 10. Our data suggested hyperglycemia partially contribute to the diabetic cardiac damage via increasing 4HNE protein adducts. Alda-1 (10 mg/kg/day) treatment further augmented ALDH2 activity, reduced 4HNE adducts and improved cardiac function in EMP-treated ALDH2*2 mice. Thus hyperglycemia mediated secondary events in type-2 DM are significant pathomechanism of the cardiac damage. In conclusion, we propose ALDH2 activation may ameliorate diabetic patients from cardiac complications who receive glucose lowering treatments.

Inheritance of diabetes mellitus as consequence of gestational hyperglycemia in rats

Inheritance of diabetes mellitus as consequence of gestational hyperglycemia in rats

The spontaneous-diabetes rat: A model of noninsulin dependent diabetes mellitus.

We succeeded to produce spontaneous-diabetes rats from normal Wistar rats by repetition of the selective breeding. Oral glucose tolerance test was used for the selection as an indicator. The result indicates that the inheritance of diabetes mellitus is not determined by specific gene(s) but is influenced by many genes relating to carbohydrate metabolism.

THE FAMILIAL OCCURRENCE OF HYPERTENSION AND CORONARY ARTERY DISEASE, WITH OBSERVATIONS CONCERNING OBESITY AND DIABETES

Excerpt I. INTRODUCTION It is commonly thought that certain families are afflicted with high blood pressure, strokes and heart attacks with unwarranted frequency and to a severe degree. Sudden deat...

The inheritance of diabetes mellitus: an analysis of the family histories of 1,631 diabetics.

The inheritance of diabetes mellitus: an analysis of the family histories of 1,631 diabetics.