Hepatic glycolytic and gluconeogenic enzymes of the obese-hyperglycemic mouse

Seidman, Irving; Horland, Allan A.; Teebor, George W.

doi:10.1016/0005-2744(67)90249-5

Cited by 35 publications

(20 citation statements)

References 11 publications

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“…This was accompanied by an additional increase in the activities of the gluconeogenic enzymes and by a decrease in pyruvate kinase, suggesting that the rise in pyruvate kinase activity was caused by elevated insulin and that insulin, although unable to normalize the activities of the gluconeogenic enzymes, had partially inhibited them. In adult ob/ob (8) and KK (6) mice the pattern of liver enzymes is similar to that found in 8-wk-old db/db mice.…”

supporting

confidence: 76%

“…Efforts to identify the defects that cause hepatic insulin resistance have involved, among others, measurement of the activity of key enzymes of the gluconeogenic, glycolytic, or lipogenic pathways (4)(5)(6)(7)(8). For example, in the db/db mouse, the gluconeogenic enzymes PEPCK, fructose-1,6-bisphosphatase, and glucose-6-phosphatase were shown to be elevated from an early age despite mild hyperinsulinemia (4).…”

mentioning

confidence: 99%

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Impaired Regulation of Hepatic Fructose-1,6-Bisphosphatase in the New Zealand Obese Mouse Model of NIDDM

Andrikopoulos

Rosella²,

Gaskin³

et al. 1993

Diabetes

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The New Zealand obese mouse, a model of NIDDM, is characterized by hyperglycemia, hyperinsulinemia, and hepatic and peripheral insulin resistance. The aim of this study was to investigate the biochemical basis of hepatic insulin resistance in NZO mice. Glycolytic and gluconeogenic enzyme activities were measured in fed and overnight fasted 19- to 20-wk-old NZO and control New Zealand chocolate mice. The NZO mice were twice as heavy as the NZC mice. The activity of the glycolytic enzymes glucokinase and pyruvate kinase was higher, whereas that of the gluconeogenic enzymes PEPCK and glucose-6-phosphatase was lower in fed and fasted NZO mice. These enzyme changes are consistent with a normal response to the hyperinsulinemia in NZO mice. In contrast, the activity of the third regulated gluconeogenic enzyme, fructose-1,6-bisphosphatase, was similar in fed and fasted NZO and NZC mice despite the higher insulin and glucose levels in the NZO mouse. This enzyme is primarily regulated by the powerful inhibitor fructose-2,6-bisphosphate. The levels of this metabolite were measured and found to be increased in both the fed and fasted states in the NZO mouse, suggesting that the activity of the bifunctional enzyme that regulates the level of inhibitor (6-phosphofructo-2-kinase/fructose-2,6- bisphosphatase) is normally regulated in the NZO mouse. We conclude that most insulin-responsive gluconeogenic and glycolytic enzymes are normally regulated in the NZO mouse, but an abnormality in the regulation of fructose-1,6-bisphosphatase may contribute to the increase hepatic glucose production in these mice.

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supporting

confidence: 76%

mentioning

confidence: 99%

Impaired Regulation of Hepatic Fructose-1,6-Bisphosphatase in the New Zealand Obese Mouse Model of NIDDM

Andrikopoulos

Rosella²,

Gaskin³

et al. 1993

Diabetes

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“…It was shown in the 1970s that the level of FBPase enzyme activity was double in patients with type 2 diabetes compared with nondiabetics (9), and this increase in FBPase has been confirmed in several animal models of obesity and insulin resistance (2,6,32,33,35,39). Moreover, studies in patients with type 2 diabetes showed increased glycerol gluconeogenesis (27), which was proposed to be caused by an increase in FBPase activity (9).…”

Section: Discussionmentioning

confidence: 92%

“…This was a surprising result, considering the human studies mentioned previously and results from our laboratory and others. These studies showed liver FBPase expression and/or activity to be double that of controls in several models of insulin resistance and obesity including New Zealand obese (NZO) mice (2), db/db mice (6), ob/ob mice (32,33), fa/fa rats (39), and high-fat (HF) fed (HFF) mice and rats (2,35), and in liver biopsies from patients with type 2 diabetes (9).…”

mentioning

confidence: 99%

Increased glucose production in mice overexpressing human fructose-1,6-bisphosphatase in the liver

Visinoni¹,

Fam²,

Blair³

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

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Increased endogenous glucose production (EGP) predominantly from the liver is a characteristic feature of type 2 diabetes, which positively correlates with fasting hyperglycemia. Gluconeogenesis is the biochemical pathway shown to significantly contribute to increased EGP in diabetes. Fructose-1,6-bisphosphatase (FBPase) is a regulated enzyme in gluconeogenesis that is increased in animal models of obesity and insulin resistance. However, whether a specific increase in liver FBPase can result in increased EGP has not been shown. The objective of this study was to determine the role of upregulated liver FBPase in glucose homeostasis. To achieve this goal, we generated human liver FBPase transgenic mice under the control of the transthyretin promoter, using insulator sequences to flank the transgene and protect it from site-of-integration effects. This resulted in a liver-specific model, as transgene expression was not detected in other tissues. Mice were studied under the following conditions: 1) at two ages (24 wk and 1 yr old), 2) after a 60% high-fat diet, and 3) when bred to homozygosity. Hemizygous transgenic mice had an approximately threefold increase in total liver FBPase mRNA with concomitant increases in FBPase protein and enzyme activity levels. After high-fat feeding, hemizygous transgenics were glucose intolerant compared with negative littermates ( P < 0.02). Furthermore, when bred to homozygosity, chow-fed transgenic mice showed a 5.5-fold increase in liver FBPase levels and were glucose intolerant compared with negative littermates, with a significantly higher rate of EGP ( P < 0.006). This is the first study to show that FBPase regulates EGP and whole body glucose homeostasis in a liver-specific transgenic model. Our homozygous transgenic model may be useful for testing human FBPase inhibitor compounds with the potential to treat patients with type 2 diabetes.

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“…In pair-feeding experiments, glucose production in isolated perfused livers of obese mice was similar to lean control (38). Furthermore, Seidmann, Horland and Teebor (35) reported that G6Pase and FDPase were elevated in both obob mice and gold thioglucose treated hyperphagic mice. Our studies and those of Seidmann, Horland and Teebor (35) indicate that the shift in the gluconeogenic enzyme profile of obese mice was primarily related to excessive dietary intake and not directly associated with a primary genetic lesion.…”

mentioning

confidence: 97%