Glucokinase Gene Locus Transgenic Mice Are Resistant to the Development of Obesity-Induced Type 2 Diabetes

Abstract

Transgenic mice that overexpress the entire glucokinase (GK) gene locus have been previously shown to be mildly hypoglycemic and to have improved tolerance to glucose. To determine whether increased GK might also prevent or diminish diabetes in diet-induced obese animals, we examined the effect of feeding these mice a high-fat high-simple carbohydrate low-fiber diet (HF diet) for 30 weeks. In response to this diet, both normal and transgenic mice became obese and had similar BMIs (5.3 ؎ 0.1 and 5.0 ؎ 0.1 kg/m 2 in transgenic and nontransgenic mice, respectively). The blood glucose concentration of the control mice increased linearly with time and reached 17.0 ؎ 1.3 mmol/l at the 30th week. In contrast, the blood glucose of GK transgenic mice rose to only 9.7 ؎ 1.2 mmol/l at the 15th week, after which it returned to 7.6 ؎ 1.0 mmol/l by the 30th week. The plasma insulin concentration was also lower in the GK transgenic animals (232 ؎ 79 pmol/l) than in the controls (595 ؎ 77 pmol/l), but there was no difference in plasma glucagon concentrations. Together, these data indicate that increased GK levels dramatically lessen the development of both hyperglycemia and hyperinsulinemia associated with the feeding of an HF diet. Diabetes 50:622-629, 2001

Long-term overexpression of glucokinase in the liver of transgenic mice leads to insulin resistance

“…In contrast, overexpression of one copy of the GK gene slightly lowers hyperglycaemia and hyperinsulinaemia induced by a high-fat diet [9]. However, these mice also overexpressed GK in beta cells [18] whereas in the present study, transgenic mice specifically overexpressed GK in the liver.…”

“…This leads to normalization of blood glucose in the absence of insulin [8]. Furthermore, a high-fat diet did not induce diabetes in transgenic mice overexpressing one copy of the GK gene [9]. In these mice, hepatic GK overexpression reduced hyperglycaemia and hyperinsulinaemia induced by a high-fat diet.…”

Improved metabolic disorders of insulin receptor-deficient mice by transgenic overexpression of glucokinase in the liver

“…Hyperglycaemia is the main factor responsible for the development of diabetes-associated retinal, renal, neurological and vascular complications [25]. Overexpression of GK in the liver of transgenic mice has been shown to prevent the development of streptozotocin-induced diabetic alterations or high-fat dietinduced hyperglycaemia [15,16,17]. Moreover, mice carrying liver-specific GK gene disruption showed decreased hepatic glucose uptake and were moderately hyperglycaemic [26].…”

“…These transgenic mice showed lower fasting blood glucose concentrations, improved glucose tolerance and increased glycogen synthesis in the liver as compared to wild-type (wt) mice. More importantly, it was shown that GK overexpression in the liver prevents the development of hyperglycaemia or diabetes induced by streptozotocin or a high-fat diet [15,16,17].…”

Deriving at candidate genes of metabolic stress from pancreas of WNIN/GR-Ob mutant rats

“…Decreased expression of Glucokinase (-1.93 fold) is also associated with hyperglycemia and IGT. 32 Nfyb, a transcription factor which promotes basal transcription of rat pyruvate carboxylase gene in β-cells, also showed an increase in the present study, and the mechanism needs to be understood. Retinoic Acid (RA) well characterized differentiation agent is known to improve pancreatic β-cells function in the following ways: (1) facilitating glucose stimulated insulin release in vitamin A depleted rats, 33 (2) induces biphasic glucose stimulated insulin secretion in human fetal pancreas explants, 33 (3) enhances insulin production in insulin secreting cell lines, 33 (4) increases glucokinase activity and gene expression levels in primary rat islets culture and insulinoma cell lines.…”