Efficacy and safety of givosiran for acute hepatic porphyria: Final results of the randomized phase III ENVISION trial.

Background & Aims: Acute hepatic porphyria (AHP) is caused by defects in hepatic heme biosynthesis, leading to disabling acute neurovisceral attacks and chronic symptoms. In ENVISION (NCT03338816), givosiran treatment for 6 months reduced attacks and other disease manifestations compared with placebo. Herein, we report data from the 36-month final analysis of ENVISION.

Cohort profile: the Funen Diabetes Database-a population-based cohort of patients with diabetes in Denmark.

Purpose: Detailed population-based data are essential to understanding the epidemiology of diabetes and its clinical course. This article describes the Funen Diabetes Database (FDDB). The purpose of the FDDB was to serve as a shared electronic medical record system for healthcare professionals treating patients with diabetes.

Diagnosing diabetes mellitus in patients with porphyria cutanea tarda.

The prevalence of diabetes mellitus is increased in patients with porphyria cutanea tarda. Different tests are available for diagnosing and screening for type II diabetes mellitus, however choosing the most suitable test is challenging. The pitfalls in the different tests along with the interfering comorbidities and treatments concerning patients with porphyria cutanea tarda complicate diagnosing these patients with diabetes mellitus.

Endogenous glucose production increases in response to metformin treatment in the glycogen-depleted state in humans: a randomised trial.

Aims/hypothesis: Metformin is believed to reduce glucose levels primarily by inhibiting hepatic glucose production. Recent data indicate that metformin antagonises glucagon-dependent glucose output, suggesting that compensatory mechanisms protect against hypoglycaemia. Here, we examined the effect of metformin on glucose metabolism in humans after a glycogen-depleting fast and the role of reduced-function alleles in OCT1 (also known as SLC22A1).

Steady-state pharmacokinetics of metformin is independent of the OCT1 genotype in healthy volunteers.

Purpose: The aim of the study was to determine the steady-state pharmacokinetics of metformin in healthy volunteers with different numbers of reduced-function alleles in the organic cation transporter 1 gene (OCT1).

Methods: The study was conducted as part of a randomized cross-over trial. Thirty-four healthy volunteers with known OCT1 genotypes (12 with two wild-type alleles, 13 with one and 9 with two reduced-function alleles) were included.

Glucose effectiveness and insulin sensitivity measurements derived from the non-insulin-assisted minimal model and the clamp techniques are concordant.

Background: We investigated the concordance between glucose effectiveness (SG) and insulin sensitivity (SI), derived from the unmodified dynamic non-insulin-assisted intravenous glucose tolerance test (IVGTT) implemented by SG(MM) and SI(MM); simulation analysis and modelling/conversational interaction (SAAM/CONSAM) versus the eu/hyperglycaemic basal insulinaemic and the euglycaemic hyperinsulinaemic clamp (SG(CLAMP) and SI(CLAMP)).

Methods: Twenty-seven of 30 normoglycaemic subjects completed a (1) euglycaemic hyperinsulinaemic clamp, (2) 6-h eu/hyperglycaemic near-normoinsulinaemic pancreatic clamp with hyperglycaemia present over the final 2 h of the clamp (Day 2 study), (3) identical clamp to (2) but with euglycaemia maintained over the entire 6 h (Day 3 study) and (4) IVGTT. SG(CLAMP) was calculated in two ways based on data from study (2) alone (Day 2 SG(CLAMP210-240')) or from data from study day (2) and (3) (Day 2-3 SG(CLAMP330-360')).

Evidence-based insulin treatment in type 1 diabetes mellitus.

Aim: Evaluation of the evidence base for recommending different insulin treatment regimens in type 1 diabetes.

Methods: A computerised literature survey was conducted using The Cochrane Controlled Trials Register and the Pub Med database for the period of 1982-2007.

Results: A meta-analysis on only 49 out of 1295 references showed that CSII compared with conventional or multiple insulin injections therapy demonstrated a significant reduction in mean HbA1c (primary outcome) of 1.

Hepatic autoregulation: response of glucose production and gluconeogenesis to increased glycogenolysis.

The effect of increased glycogenolysis, simulated by galactose's conversion to glucose, on the contribution of gluconeogenesis (GNG) to hepatic glucose production (GP) was determined. The conversion of galactose to glucose is by the same pathway as glycogen's conversion to glucose, i.e.

Effects of troglitazone in young first-degree relatives of patients with type 2 diabetes.

Objective: Insulin resistance is a key characteristic of first-degree relatives of patients with type 2 diabetes. We therefore treated young, glucose-tolerant relatives with the insulin action enhancer troglitazone in order to determine the effects on insulin sensitivity, glucose metabolism, and glycogen synthase activity.

Research Design And Methods: Relatives were randomized in a double-blind manner and treated for 12 weeks with either 200 mg troglitazone or placebo.

The combined effect of triple therapy with rosiglitazone, metformin, and insulin aspart in type 2 diabetic patients.

Objective: Type 2 diabetes is caused by reduced insulin secretion and insulin resistance in skeletal muscle and liver. We tested the combination therapy with insulin aspart, rosiglitazone, and metformin with the purpose of treating all three defects in order to test the hypothesis that this "triple therapy" will normalize glucose metabolism.

Research Design And Methods: Sixteen obese type 2 diabetic outpatients on human NPH or MIX (regular + NPH insulin) insulin twice daily were randomized to either triple therapy, i.

Does overnight normalization of plasma glucose by insulin infusion affect assessment of glucose metabolism in Type 2 diabetes?

Aims: In order to perform euglycaemic clamp studies in Type 2 diabetic patients, plasma glucose must be reduced to normal levels. This can be done either (i) acutely during the clamp study using high-dose insulin infusion, or (ii) slowly overnight preceding the clamp study using a low-dose insulin infusion. We assessed whether the choice of either of these methods to obtain euglycaemia biases subsequent assessment of glucose metabolism and insulin action.

Is hepatic glucose production increased in type 2 diabetes mellitus?

Based on recent studies, including our own, using what we consider to be an appropriate technique to estimate rates of hepatic glucose production (HGP), this article can be summarized as follows: 1) HGP in the overnight fasted state is near normal in obese type 2 diabetes (T2D) subjects, i.e., it may be increased by a mean of 12% compared to matched control subjects.

Effects of free fatty acids per se on glucose production, gluconeogenesis, and glycogenolysis.

Insulin-independent effects of a physiological increase in free fatty acid (FFA) levels on fasting glucose production, gluconeogenesis, and glycogenolysis were assessed by administering [6,6-(2)H(2)]-glucose and deuteriated water ((2)H(2)O) in 12 type 1 diabetic patients, during 6-h infusions of either saline or a lipid emulsion. Insulin was either fully replaced (euglycemic group, n = 6), or underreplaced (hyperglycemic group, n = 6). During saline infusions, plasma FFA levels remained unchanged.

Assessment of hepatic insulin action in obese type 2 diabetic patients.

Defects in hepatic insulin action in type 2 diabetes and its possible underlying mechanisms were assessed in euglycemic-hyperinsulinemic clamp studies, using improved tracer methods (constant specific activity technique). Ten obese diabetic patients (age 54 years, BMI 29 +/- 0.5 kg/m(2)) and ten matched control subjects were studied at baseline (after an overnight fast) and during insulin infusions of 20- and 40-mU.

DGGE analysis of the coproporphyrinogen oxidase gene: two new mutations in DNA from Danish patients with hereditary coproporphyria.

The knowledge of at least 21 different mutations and several polymorphisms in the coproporphyrinogen oxidase (CPO) gene demonstrates that the molecular basis of hereditary coproporphyria is heterogeneous. We developed a DGGE-based assay for the analysis of exons 2 to 7, including 14-96 nucleotides of the flanking intronic sequences of the CPO gene. To render it suitable for the clinical diagnostic laboratory, we designed the assay to allow use of identical PCR conditions and the same DGGE gel for analyses of all the regions.

Hyperglycaemia enhances renal magnesium excretion in type 1 diabetic patients.

Magnesium depletion is a common feature of diabetes mellitus, apparently related to glycaemic control. The aim of the study was to investigate the isolated effect of hyperglycaemia upon renal magnesium excretion. Urinary magnesium excretion rates were measured in 10 patients with Type 1 diabetes mellitus on two different days with different levels of blood glucose concentration but equal plasma insulin concentration.

Glucose-mediated glucose disposal in insulin-resistant normoglycemic relatives of type 2 diabetic patients.

With the aim of investigating glucose-mediated glucose disposal (glucose effectiveness [GE]) in 15 (3 female and 12 male subjects) insulin-resistant normoglycemic relatives of patients with type 2 diabetes (DM2), and 15 age-, sex-, and BMI-matched control subjects without a family history of DM2, we performed 2 studies: 1) a 5-h euglycemic near-normoinsulinemic pancreatic clamp with somatostatin (360 microg/h), insulin (0.25 mU x kg(-1) x min(-1)), glucagon (0.5 ng x kg(-1) x min(-1)), growth hormone (6 ng x kg(-1) x min(-1)), and tritiated glucose infusion and indirect calorimetry; and 2) on a separate day, an identical 5-h clamp but at hyperglycemia (approximately 12 mmol/l) over the last 2 h.

Impact of ubiquinone (coenzyme Q10) treatment on glycaemic control, insulin requirement and well-being in patients with Type 1 diabetes mellitus.

Aim: To investigate the effect of ubiquinone (coenzyme Q10) on glycaemic control and insulin requirement in patients with Type 1 diabetes mellitus (DM).

Methods: We investigated 34 patients with Type 1 DM in a randomized, double-blind, placebo-controlled study. Patients received either 100 mg Q10 or placebo daily for 3 months.

Irreversibility of the defect in glycogen synthase activity in skeletal muscle from obese patients with NIDDM treated with diet and metformin.

Objective: To assess the reversibility of the defect in glycogen synthase (GS) activity in skeletal muscle from obese patients with NIDDM treated with a hypocaloric diet and metformin.

Research Design And Methods: Eighteen obese patients newly diagnosed with NIDDM were included in a randomized placebo-controlled double-blind parallel group trial and followed for 3 months. Euglycemic-hyperinsulinemic clamp including indirect calorimetry and biopsy of m.

Impaired insulin-stimulated nonoxidative glucose metabolism in pancreas-kidney transplant recipients. Dose-response effects of insulin on glucose turnover.

Insulin resistance is a characteristic feature in recipients of a pancreas transplant, but the relative contribution of the liver and peripheral tissues to this abnormality within a spanning range of insulin concentrations is unknown. To assess the impact of insulin action on glucose metabolism after pancreas transplantation, a euglycemic-hyperinsulinemic clamp with sequential insulin infusions (5, 40, and 200 mU.m-2.

Effects of insulin on glucose turnover rates in vivo: isotope dilution versus constant specific activity technique.

The conventional isotope dilution technique was compared with the more accurate constant specific activity (SA) method at six different insulin levels. Paired euglycemic clamp studies were performed in 30 normal subjects (4-hour insulin infusion: 5, 10, 20, 40, 80, and 160 mU . m-2 .

Pathophysiology of non-insulin-dependent diabetes mellitus (NIDDM).

In this review, the pathophysiologycal events leading to hyperglycemia in NIDDM patients are discussed, i.e. glucose effectiveness, insulin action (in muscle and liver) and insulin secretion.