Search

Aims Insulin resistance and impaired insulin secretion are cardinal defects that contribute to hyperglycemia in type 2 diabetes. Recently, a new class of drugs called sodium-glucose linked transporter 2 (SGLT2) inhibitors has been introduced that reduce blood glucose by inhibiting glucose reabsorption in the kidney and is not dependent on glucose metabolism or insulin action. The purpose of the present study was to determine whether the excretion of glucose would improve insulin resistance, impaired insulin secretion or both. Materials and Methods Appropriate methods were used to assess insulin sensitivity (euglycemic/hyperinsulinemic clamp) and insulin secretion (hyperglycemic clamp) in insulin resistant and hyperglycemic PEPCK transgenic rats following treatment with the SGLT2 inhibitor dapagliflozin. Results In 14-week old animals with hyperglycemia, insulin resistance and glucose intolerance, 6 weeks dapagliflozin treatment resulted in lower weight gain, plasma glucose and insulin levels, improved glucose tolerance associated with enhanced insulin sensitivity (Rate of glucose disappearance: 51.6 ± 2.3 vs 110.6 ± 3.9 µmol/min/kg, P

Increased glucose production is associated with fasting hyperglycaemia in type 2 diabetes but whether or not it causes glucose intolerance is unclear. This study sought to determine whether a primary defect in gluconeogenesis (GNG) resulting in elevated glucose production is sufficient to induce glucose intolerance in the absence of insulin resistance and impaired insulin secretion. Progression of glucose intolerance was assessed in phosphoenolpyruvate carboxykinase (PEPCK) transgenic rats, a genetic model with a primary increase in GNG. Young (4–5 weeks of age) and adult (12–14 weeks of age) PEPCK transgenic and Piebald Virol Glaxo (PVG/c) control rats were studied. GNG, insulin sensitivity, insulin secretion and glucose tolerance were assessed by intraperitoneal and intravascular substrate tolerance tests and hyperinsulinaemic/euglycaemic clamps. Despite elevated GNG and increased glucose appearance, PEPCK transgenic rats displayed normal glucose tolerance due to adequate glucose disposal and robust glucose-mediated insulin secretion. Glucose intolerance only became apparent in the PEPCK transgenic rats following the development of insulin resistance (both hepatic and peripheral) and defective glucose-mediated insulin secretion. Taken together, a single genetic defect in GNG leading to increased glucose production does not adversely affect glucose tolerance. Insulin resistance and impaired glucose-mediated insulin secretion are required to precipitate glucose intolerance in a setting of chronic glucose oversupply.

Type 2 diabetes (T2D) is associated with defective insulin secretion, which in turn contributes to worsening glycaemic control and disease progression. The genetic cause(s) associated with impaired insulin secretion in T2D are not well elucidated. Here we used the polygenic New Zealand Obese (NZO) mouse model, which displays all the cardinal features of T2D including hyperglycaemia to identify genes associated with β-cell dysfunction. A genome-wide scan identified a major quantitative trait locus (QTL) on chromosome 7 associated with defective glucose-mediated insulin secretion. Using congenic strains, the locus was narrowed to two candidate genes encoding the components of the KATP channel: Abcc8 (SUR1) and Kcnj11 (Kir6.2). The NZO Abcc8 allele was associated with a ∼211 bp deletion in its transcript and reduced expression of SUR1. Transgenic NZO mice were generated that expressed the WT Abcc8/Kcnj11 genes and displayed significant improvements in early-phase glucose-mediated insulin secretion and glucose tolerance, confirming Abcc8 as a causative gene. Importantly, we showed that despite improving β-cell function in the NZO transgenic mice, there was no enhancement of insulin sensitivity or body weight. This study provides evidence for a role of Abcc8 in early-phase glucose-mediated insulin secretion and validates this gene as a contributor to β-cell dysfunction in T2D.

Liver fructose-1,6-bisphosphatase (FBPase) is a regulatory enzyme in gluconeogenesis that is elevated by obesity and dietary fat intake. Whether FBPase functions only in glucose metabolism or has other metabolic roles is currently unclear. In our recently published study, we examined the importance of liver FBPase in body weight regulation by performing a series of comprehensive physiological and biochemical assessments of energy balance and specific intervention studies in our transgenic mouse line that overexpresses FBPase specifically in the liver. Compared with negative littermates, these FBPase transgenic mice weighed 10% less, had 50% less adiposity, ate 15% less food but did not have altered energy expenditure. Increased circulating leptin and cholecystokinin levels, elevated fatty acid oxidation and reduced appetite stimulating neuropeptides, neuropeptide Y (NPY) and agouti-related peptide (AGRP), underpinned this phenotype. Blocking the action of FBPase returned food intake and body weight to those of the negative littermates. Our study is the first to identify liver FBPase as a previously unknown regulator of appetite and adiposity. Importantly, this work recognizes the liver as an important organ in appetite and body weight regulation. This commentary will provide further insight and expand on this novel concept that the liver does in fact play an important role in adiposity.

Liver fructose-1,6-bisphosphatase (FBPase) is a regulatory enzyme in gluconeogenesis that is elevated by obesity and dietary fat intake. Whether FBPase functions only to regulate glucose or has other metabolic consequences is not clear; therefore, the aim of this study was to determine the importance of liver FBPase in body weight regulation. To this end we performed comprehensive physiologic and biochemical assessments of energy balance in liver-specific transgenic FBPase mice and negative control littermates of both sexes. In addition, hepatic branch vagotomies and pharmacologic inhibition studies were performed to confirm the role of FBPase. Compared with negative littermates, liver-specific FBPase transgenic mice had 50% less adiposity and ate 15% less food but did not have altered energy expenditure. The reduced food consumption was associated with increased circulating leptin and cholecystokinin, elevated fatty acid oxidation, and 3-β-hydroxybutyrate ketone levels, and reduced appetite-stimulating neuropeptides, neuropeptide Y and Agouti-related peptide. Hepatic branch vagotomy and direct pharmacologic inhibition of FBPase in transgenic mice both returned food intake and body weight to the negative littermates. This is the first study to identify liver FBPase as a previously unknown regulator of appetite and adiposity and describes a novel process by which the liver participates in body weight regulation.

We thank Masotti (1) for his interest and comment in this issue of Diabetes on our recently published article (2). In his letter, Masotti proposed, on the basis of our study findings and those from his own laboratory, that the glycolytic/gluconeogenic pathways may play an integral role in body weight regulation. Fructose-1,6-bisphosphate is not only the key substrate in gluconeogenesis for fructose-6-phosphate production but is also the substrate for the production of glyceraldehyde-3-phosphate and dihydroxyacetone phosphate via the enzyme aldolase A ( ALDOA )—a glycolytic-pathway activated reaction. Masotti and colleagues (3) recently demonstrated that increased expression of microRNA-122 was associated with the development of nonalcoholic fatty liver disease in rats fed a …