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.

Diurnal rhythm in endogenous glucose production is a major contributor to fasting hyperglycaemia in type 2 diabetes. Suprachiasmatic deficit or limit cycle behaviour?

Aims/hypothesis: An increase in endogenous glucose production (EGP) is a major contributor to fasting morning hyperglycaemia in type 2 diabetes. This increase is dissipated with fasting, later in the day. To understand its origin, EGP, gluconeogenesis and hormones that regulate metabolism were measured over 24 h.

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.

Mild acute renal failure potentiates metformin accumulation in the diabetic rat kidney without further impairment of renal function.

Objectives: To analyze, in acute renal failure (ARF) in diabetic rats, how moderate functional ARF would modify metformin (MET) pharmacokinetics and if plasma and renal tissue MET accumulation could aggravate renal insufficiency and/or elicit plasma lactate accumulation.

Methods: Streptozotocin-induced diabetic rats were allocated to four groups: control, MET, ARF, ARF-MET (6-7 rats per group). MET (100 mg/kg/day) was given per os for two weeks before ARF was induced by drinking restriction and enalapril treatment.

Quantitation of basal endogenous glucose production in Type II diabetes: importance of the volume of distribution.

The rate of endogenous glucose production (EGP) is important in understanding the pathophysiology of Type II (non-insulin-dependent) diabetes mellitus, the aetiology of its complications, and the identification of potential therapeutic targets. A great deal of effort has therefore been expended in its evaluation. Most measurements in humans have been made using tracers, or labelled analogues of glucose.

Inverse relationship between peripheral insulin removal and action: studies with metformin.

The interaction of insulin with metformin on muscle glucose metabolism was examined in the perfused rat hindquarter. Glucose, lactate, and insulin were measured at the inflow to and outflow from the hindquarter, which was perfused with human erythrocytes suspended in a Kreb's-Ringer albumin buffer for 120 min. Perfusions were performed with no additions (I) and with insulin infusions targeted to concentrations of 175 (II) and 350 pmol/l (III) as well as infusions targeted to levels of 0 (IV), 70 (V), and 175 pmol/l (VI) but in the presence of metformin (90 microg/ml).

Hepatic glucose uptake, gluconeogenesis and the regulation of glycogen synthesis.

Hepatic glycogen is replenished during the absorptive period postprandially. This repletion is prompted partly by an increased hepatic uptake of glucose by the liver, partly by metabolite and hormonal signals in the portal vein, and partly by an increased gluconeogenic flux to glycogen (glyconeogenesis). There is some evidence that the direct formation of glycogen from glucose and that formed by gluconeogenic pathways is linked.

Production and metabolic clearance of glucose under basal conditions in Type II (non-insulin-dependent) diabetes mellitus.

Aims/hypothesis: The pathogenesis of fasting hyperglycaemia in Type II (non-insulin-dependent) diabetes mellitus has yet to be clarified. Rates of glucose production (Ra), utilization and metabolic clearance rate were therefore measured during an extended fast, in control subjects and in Type II diabetic patients.

Methods: Nine subjects with newly-diagnosed or diet-treated diabetes and seven control subjects matched for age and weight (BMI 36.

Insulin sensitivity and its measurement: structural commonalities among the methods.

Insulin is the principal hormone of metabolic regulation. Reduced responses to insulin constitute an underlying feature of type 2 diabetes. It is, therefore, incumbent on those who work in this area (as well as many others) to characterize this response, in as simple and consistent a way as possible, so that this measure can be used both in the investigational and clinical setting.

Effect of acarbose on insulin sensitivity in elderly patients with diabetes.

Objective: To study the effect of acarbose, an alpha-glucosidase inhibitor, on insulin release and insulin sensitivity in elderly patients with type 2 diabetes.

Research Design And Methods: Elderly patients with type 2 diabetes were randomly treated in a double-blind fashion with placebo (n = 23) or acarbose (n = 22) for 12 months. Before and after randomization, subjects underwent a meal tolerance test and a hyperglycemic glucose clamp study designed to measure insulin release and sensitivity.

Preparation of a microcrystalline suspension formulation of Lys(B28)Pro(B29)-human insulin with ultralente properties.

The monomeric analogue, Lys(B28)Pro(B29)-human insulin (LysPro), has been crystallized using similar conditions employed to prepare extended-acting insulin ultralente formulations. In the presence of zinc ions, sodium acetate and sodium chloride, but without phenolic preservative, LysPro surprisingly forms small rhombohedral crystals with similar morphology to human insulin ultralente crystals with a mean particle size of 20 +/- 1 microm. X-ray powder diffraction studies on the LysPro crystals prior to dilution in ultralente vehicle ([NaCl] = 1.

Measurement of gluconeogenesis and mass isotopomer analysis based on [U-(13)C]glucose.

Two methods of measuring rates of gluconeogenesis based on label redistribution after the introduction of [U-(13)C]glucose into the whole body are examined. These methods are compared with methods previously derived for carbon-14 tracers. It is shown that the three approaches (stoichiometric, dilution, and combinatorial) are equivalent, provided the same set of assumptions are used.

Inappropriately high plasma insulin levels in suspected perinatal asphyxia.

The aim of this study was to determine differences in levels of the major hormones responsible for glucose homeostasis (insulin and glucagon) in babies with acute neonatal encephalopathy secondary to perinatal asphyxia and to correlate these with outcome. In a prospective observational study, plasma insulin, C-peptide, glucagon and serum glucose levels were determined using standard techniques at specified times in term babies with a diagnosis on admission of perinatal asphyxia or acute neonatal encephalopathy. The setting comprised two university-affiliated, regional, tertiary level neonatal intensive care units.

Preparation and characterization of a cocrystalline suspension of [LysB28,ProB29]-human insulin analogue.

Soluble preparations of [LysB28,ProB29]-human insulin analogue (LysPro) exhibit more rapid absorption than human insulin upon subcutaneous injection. Biphasic mixtures of LysPro and intermediate-acting insulin suspensions could provide advantages over current preparations for the treatment of diabetes. To prepare biphasic mixtures of LysPro, a suspension formulation of the analogue is required.