Abnormalities in hepatic enzyme activities during development of diabetes in db mice

Abstract

Summary. Seven hepatic enzymes were assayed in vitro in diabetic and control C57BL/Ks mice at 1, 2, and 41/2 month. An elevation in phosphoenolpyruvate carboxykinase and glueose-6-phosphatase was observed before the onset of hyperglycemia in db mice at the age of 1 month. At two months, these mice had hyperglycemia, hyperinsulinemia aud high levels of phosphoenolpyruvate carboxykinase, glucose-6-phosphatase, fruetose-l,6-diphosphatase, pyruvate kinase and 6-phosphogluconate dehydrogenase. The 41/2 month old db mice had normal plasma insulin, severe hyperglycemia, exorbitant amount of hepatic gluconeogenie enzymes and reduced quantity of glycolytic and pentose-phosphate shunt enzymes. The disturbance in enzyme activities and blood sugar was partially controlled by placing the animals on a limited diet beginning at the age of 1 month. In rive studies indicated that hyperglycemia resulted, at least in part, from an accelerated rate of gluconeogenesis. The development of diabetes in these mice is discussed with reference to these findings. Anomalies d'activit~s enzymatiques h~patlques pendant le d~veloppement du diab~te chez [a souris dbRdsum~. 7 enzymes hdpatiques ont gtd dtudi6s in vibro chez les souris diab@tiques et contr61es de la souehe C57BL/Ks, ~ l'~ge de 1, 2, et 4 mois et demi. Avant l'apparition de l'hyperglyc6mie, une augmentation de la phospho6nolpyruvate carboxykinase et de la glucose-6-phosphatase a dr6 observde chez la souris db agde d'un mois./k l'&ge de 2 reels, cos sourls pr6sentaient une hyperglyc6mie, une hyperinsulin@mie et une activit6 accrue de la phospho6nolpyruvate carboxykinase, de la glucose-6-phosphatase, de la fruetose-l,6-diphosphatase, de la pyruvate kinase et de la 6-phosphogluconate d@liydro-ggnase. Chez los souris db de 4 mois et demi, on a observ6 des taux normaux d'insulindmie, une hyperglycdmie s@v@re, une activit6 extr~mement @levde des enzymes de la glucon6og@n~se h6patique et extr@mement r6duite de ceux de la glycolyse et du cycle des pentoses. Les dgsordres de ces enzymes ainsi que Iceux~ du glucose sanguin ont pu @tre contr61es partielleuent ell soumettaut les animaux ~ une restriction alimentaire d@s l'&ge d'un mois. Des 6tudes in vivo ont indiqu6 que l'hyperglyc6mie r6sulte, ell partie du moins, d'une glucon6o-g@n~se aec@l@r@e. L'apparition du diab&te chez la souris est discut6e ~ la lumi@re de ees r6sultats. Verd~nderungen yon Enzym-Aktlvi~ten der JLeber wdih. rend der Entwiclclung des Diabetes der dbdb MausZusammenfassung. Die Bestlmmung der Aktivit~t yon 7 Enzymen der glykolytischen und gluconeogenetischen Ketten in Leberextrakten yon 1, 2 and 4 ~ ~onate alton db/db l~usen nnd normalen Kontrolltieren ergab folgende Resultate: Bei noch normoglyks db/db ~r im Alter yon 1 l~onat waren Phosphoenolpyruvat. Carboxikinase und Glucose-6-Phosphatase-Aktivitiit erh6ht. Im Alter yon 2 l~onaten (manifesto Hyperglyk~mie und Hyperlnsulingmie) waren auger den Schliisselenzymen der Gluconeogenese auch die A~ivit~ten der Pyruvat Kinase und der 6-Phosphogluconat-Dehydrogenase erh6ht. Be...

The influence of age and dietary conditions on diabetes in the db mouse

“…By 4.5 months, the gluconeogenie enzymes had increased further but the glyeoly~ie enzymes had decreased [1]. Blood sugars of the diabetic mice were normal at 4 weeks, but increased throughout the 3--4 months of observation to a maximum of over 500 mg%.…”

“…The evidence for this is i increased conversion of glucose to COs in vivo [2], increased glucose utilization by adipose tissue, and increased glucose utiliization by liver as indicated by increased glycolytie enzymes [1]. With increased age, a number of changes occur in the db mice which result in the deterioration of their condition.…”

“…Apparently the beta cells of the db mouse were not able to meet the excessive demands for insulin as is the case of some of the other abnormal mice, such as the KK [10,4]. In the KK mouse in contrast to the db mouse, the beta cells and pancreatic islets increase in number and size resulting The elevated level of glucormogenic enzymes was partially reduced and glycolytic enzymes increased when db mice were maintained on limited diet [1].…”

“…by increased glueoneogenic enzymes and increased conversion of pyruvate to glucose [1], and 2. glucose utilization was decreased as shown by decreased glycolytic enzyme levels in the liver and decreased glucose oxidation by adipose tissue. As these conditions continued, the beta cells were apparently unable to keep up with the continuous and severe demands placed upon them: Supporting this were the observations of decreased pancreatic and plasma insulins.…”

A primary defect in glucose production alone cannot induce glucose intolerance without defects in insulin secretion

“…Insulin exerts its inhibitory actions by negatively regulating the transcription of the rate-determining enzymes phosphoenolpyruvate carboxykinase (PEPCK), fructose-1,6-bisphosphatase (FBPase) and glucose-6-phosphatase (G6Pase). Elevated GNG, stemming from impaired insulinmediated suppression of gluconeogenic enzyme transcription is a defect observed in both animals and humans with glucose intolerance and T2D (Chang & Schneider 1970, Seidman et al 1970, Arizmendi et al 1999, Gastaldelli et al 2000, Roden et al 2000, Song et al 2001, Chevalier et al 2006.…”