Sympathetic nervous dysregulation in the absence of systolic left ventricular dysfunction in a rat model of insulin resistance with hyperglycemia.

Background: Diabetes mellitus is strongly associated with cardiovascular dysfunction, derived in part from impairment of sympathetic nervous system signaling. Glucose, insulin, and non-esterified fatty acids are potent stimulants of sympathetic activity and norepinephrine (NE) release. We hypothesized that sustained hyperglycemia in the high fat diet-fed streptozotocin (STZ) rat model of sustained hyperglycemia with insulin resistance would exhibit progressive sympathetic nervous dysfunction in parallel with deteriorating myocardial systolic and/or diastolic function.

KATP channel-deficient pancreatic beta-cells are streptozotocin resistant because of lower GLUT2 activity.

In wild-type mice, a single injection of streptozotocin (STZ, 200 mg/kg body wt) caused within 4 days severe hyperglycemia, hypoinsulinemia, significant glucose intolerance, loss of body weight, and the disappearance of pancreatic beta-cells. However, in ATP-sensitive K(+) channel (K(ATP) channel)-deficient mice (Kir6.2(-/-) mice), STZ had none of these effects.

Endogenous glucose production in type 2 diabetes: basal and postprandial. Role of diurnal rhythms.

Glycemia in type 2 diabetes is characterized by a nonsteady but stable diurnal cycle. This leads to morning fasting hyperglycemia. It arises from an underlying circadian pattern in endogenous glucose production because the metabolic clearance rate of glucose is decreased but constant.

Tracer-determined glucose fluxes in health and type 2 diabetes: basal conditions.

The role of increases in basal glucose production (EGP) in the pathogenesis of hyperglycaemia in type 2 diabetes (DM2) has been controversial. It is proposed here that the differences arose from: (i) different patient populations at different stages in the evolution of the disease, (ii) a non-steady state due to diurnal variations in EGP, and measurements at different times of day, and (iii) differences in experimental techniques: tracers, priming strategies and methods of calculation. Methodologically we show that (i) non-steady-state methods and (ii) a one-compartment model with volume of distribution estimated from tracer data are necessary in DM2.

Metformin and its liver targets in the treatment of type 2 diabetes.

Although a number of assessments disagree, the preponderance of the evidence indicates that the major therapeutic action of metformin in type 2 diabetes (DM2) is on the liver, and glucose production (EGP) in particular. At the level of this organ, the actions of metformin can be characterized as pleiotropic. The major questions addressed here are therefore: (i) the methodological aspects of the determination of glucose fluxes: when glucose production is not found to be elevated in type 2 diabetes, it is not surprising that little action of metformin on this flux is found.