The biochemical basis of increased hepatic glucose production in a mouse model of type 2 (non-insulin-dependent) diabetes mellitus

Andrikopoulos, Sofianos; Proietto, Joseph

doi:10.1007/bf00400598

Cited by 54 publications

(42 citation statements)

References 56 publications

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“…This has been associated with a NEFA-induced increase in gluconeogenesis [15,16,17,18]. Recently, we have confirmed that the dietary fat-induced increase in gluconeogenesis is associated with increased levels of fructose-1,6-bisphosphatase, a regulatory enzyme in the glucose synthesising pathway [15,19]. Interestingly, it has been suggested that fat-induced hepatic insulin resistance precedes muscle insulin resistance [13] raising the possibility that hepatic insulin resistance can contribute to muscle and fat insulin resistance observed under states of increased dietary fat intake.…”

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confidence: 63%

Peripheral insulin resistance develops in transgenic rats overexpressing phosphoenolpyruvate carboxykinase in the kidney

et al. 2003

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Aims/hypothesis. To study the secondary consequences of impaired suppression of endogenous glucose production (EGP) we have created a transgenic rat overexpressing the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) in the kidney. The aim of this study was to determine whether peripheral insulin resistance develops in these transgenic rats. Methods. Whole body rate of glucose disappearance (R d ) and endogenous glucose production were measured basally and during a euglycaemic/hyperinsulinaemic clamp in phosphoenolpyruvate carboxykinase transgenic and control rats using [6-3 H]-glucose. Glucose uptake into individual tissues was measured in vivo using 2-[1-14 C]-deoxyglucose. Results. Phosphoenolpyruvate carboxykinase transgenic rats were heavier and had increased gonadal and infrarenal fat pad weights. Under basal conditions, endogenous glucose production was similar in phosphoenolpyruvate carboxykinase transgenic and control rats (37.4±1.1 vs 34.6±2.6 µmol/kg/min). Moderate hyperinsulinaemia (810 pmol/l) completely suppressed EGP in control rats (−0.6±5.5 µmol/kg/min, p<0.05) while there was no suppression in phosphoenolpyruvate carboxykinase rats (45.2±7.9 µmol/kg/min). Basal R d was comparable between PEPCK transgenic and control rats (37.4±1.1 vs 34.6±2.6 µmol/kg/min) but under insulin-stimulated conditions the increase in R d was greater in control compared to phosphoenolpyruvate carboxykinase transgenic rats indicative of insulin resistance (73.4±11.2 vs 112.0±8.0 µmol/kg/min, p<0.05). Basal glucose uptake was reduced in white and brown adipose tissue, heart and soleus while insulin-stimulated transport was reduced in white and brown adipose tissue, white quadriceps, white gastrocnemius and soleus in phosphoenolpyruvate carboxykinase transgenic compared to control rats. The impairment in both white and brown adipose tissue glucose uptake in phosphoenolpyruvate carboxykinase transgenic rats was associated with a decrease in GLUT4 protein content. In contrast, muscle GLUT4 protein, triglyceride and long-chain acylCoA levels were comparable between PEPCK transgenic and control rats. Conclusions/interpretation. A primary defect in suppression of EGP caused adipose tissue and muscle insulin resistance. [Diabetologia (2003[Diabetologia ( ) 46:1338[Diabetologia ( -1347

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confidence: 63%

Peripheral insulin resistance develops in transgenic rats overexpressing phosphoenolpyruvate carboxykinase in the kidney

et al. 2003

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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: 95%

“…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).…”

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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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“…Tritiated H 2 O was then measured by liquid scintillation counting. Glucose oxidation was estimated by assessing the formation of 14 CO 2 from the metabolism of [U- 14 C]glucose (33). The amount of 14 CO 2 was determined by liquid scintillation counting.…”

Section: Elevated Islet Fbpase Impairs Insulin Secretionmentioning

confidence: 99%

“…In addition, FBPase was upregulated fivefold in islets from the diabetes-susceptible obese BTBR mouse compared with the diabetes-resistant C57BL/6 mouse (13). We have previously shown that FBPase is upregulated in the liver of mice or rats fed a high-fat diet (14,15) and in the New Zealand Obese (NZO) mouse, an obese model of type 2 diabetes (14,16). We have recently demonstrated that transgenic mice with specific overexpression of FBPase in the liver displayed increased glycerol gluconeogenesis (17).…”

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confidence: 93%

Fructose-1,6-Bisphosphatase Overexpression in Pancreatic β-Cells Results in Reduced Insulin Secretion

et al. 2008

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OBJECTIVE-Fructose-1,6-bisphosphatase (FBPase) is a gluconeogenic enzyme that is upregulated in islets or pancreatic ␤-cell lines exposed to high fat. However, whether specific ␤-cell upregulation of FBPase can impair insulin secretory function is not known. The objective of this study therefore is to determine whether a specific increase in islet ␤-cell FBPase can result in reduced glucose-mediated insulin secretion. RESEARCH DESIGN AND METHODS-To test this hypothesis, we have generated three transgenic mouse lines overexpressing the human FBPase (huFBPase) gene specifically in pancreatic islet ␤-cells. In addition, to investigate the biochemical mechanism by which elevated FBPase affects insulin secretion, we made two pancreatic ␤-cell lines (MIN6) stably overexpressing huFBPase.RESULTS-FBPase transgenic mice showed reduced insulin secretion in response to an intravenous glucose bolus. Compared with the untransfected parental MIN6, FBPase-overexpressing cells showed a decreased cell proliferation rate and significantly depressed glucose-induced insulin secretion. These defects were associated with a decrease in the rate of glucose utilization, resulting in reduced cellular ATP levels.CONCLUSIONS-Taken together, these results suggest that upregulation of FBPase in pancreatic islet ␤-cells, as occurs in states of lipid oversupply and type 2 diabetes, contributes to insulin secretory dysfunction.

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The biochemical basis of increased hepatic glucose production in a mouse model of type 2 (non-insulin-dependent) diabetes mellitus

Cited by 54 publications

References 56 publications

Peripheral insulin resistance develops in transgenic rats overexpressing phosphoenolpyruvate carboxykinase in the kidney

Peripheral insulin resistance develops in transgenic rats overexpressing phosphoenolpyruvate carboxykinase in the kidney

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

Fructose-1,6-Bisphosphatase Overexpression in Pancreatic β-Cells Results in Reduced Insulin Secretion

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