OBJECTIVEType 2 diabetes pathophysiology is characterized by dysregulated glucagon secretion. LY2409021, a potent, selective small-molecule glucagon receptor antagonist that lowers glucose was evaluated for efficacy and safety in patients with type 2 diabetes.
RESEARCH DESIGN AND METHODSThe efficacy (HbA 1c and glucose) and safety (serum aminotransferase) of oncedaily oral administration of LY2409021 was assessed in two double-blind studies. Phase 2a study patients were randomized to 10, 30, or 60 mg of LY2409021 or placebo for 12 weeks. Phase 2b study patients were randomized to 2.5, 10, or 20 mg LY2409021 or placebo for 24 weeks.
RESULTSLY2409021 produced reductions in HbA 1c that were significantly different from placebo over both 12 and 24 weeks. After 12 weeks, least squares (LS) mean change from baseline in HbA 1c was -0.83% (10 mg), -0.65% (30 mg), and -0.66% (60 mg) (all P < 0.05) vs. placebo, 0.11%. After 24 weeks, LS mean change from baseline in HbA 1c was -0.45% (2.5 mg), -0.78% (10 mg, P < 0.05), -0.92% (20 mg, P < 0.05), and -0.15% with placebo. Increases in serum aminotransferase, fasting glucagon, and total fasting glucagon-like peptide-1 (GLP-1) were observed; levels returned to baseline after drug washout. Fasting glucose was also lowered with LY2409021 at doses associated with only modest increases in aminotransferases (mean increase in alanine aminotransferase [ALT] £10 units/L). The incidence of hypoglycemia in the LY2409021 groups was not statistically different from placebo.
CONCLUSIONSIn patients with type 2 diabetes, glucagon receptor antagonist treatment significantly lowered HbA 1c and glucose levels with good overall tolerability and a low risk for hypoglycemia. Modest, reversible increases in serum aminotransferases were observed.
In this cohort of patients with T2D, chronic glucagon receptor antagonism with LY2409021 was associated with glucose-lowering but also demonstrated increases in hepatic fat, hepatic aminotransferases, and other adverse effects.
LY showed improvement in fasting and postprandial glycaemic parameters when administered once weekly in subjects with type 2 diabetes. The pharmacokinetics and safety profiles also support further investigation of this novel agent.
Few attempts have been made to model mathematically the progression of type 2 diabetes. A realistic representation of the long-term physiological adaptation to developing insulin resistance is necessary for effectively designing clinical trials and evaluating diabetes prevention or disease modification therapies. Writing a good model for diabetes progression is difficult because the long time span of the disease makes experimental verification of modeling hypotheses extremely awkward. In this context, it is of primary importance that the assumptions underlying the model equations properly reflect established physiology and that the mathematical formulation of the model give rise only to physically plausible behavior of the solutions. In the present work, a model of the pancreatic islet compensation is formulated, its physiological assumptions are presented, some fundamental qualitative characteristics of its solutions are established, the numerical values assigned to its parameters are extensively discussed (also with reference to available cross-sectional epidemiologic data), and its performance over the span of a lifetime is simulated under various conditions, including worsening insulin resistance and primary replication defects. The differences with respect to two previously proposed models of diabetes progression are highlighted, and therefore, the model is proposed as a realistic, robust description of the evolution of the compensation of the glucose-insulin system in healthy and diabetic individuals. Model simulations can be run from the authors' web page.
A major field experiment was conducted which obtained measurements of the attenuation and transformation of short gravity waves as they cross the windward edge of an offshore coral reef. Water level data were collected for over 3000 individual time series during a wide range of environmental conditions. At the innermost measurement site, which is located on the horizontal reef flat after the completion of wave breaking, the upper bound of significant and maximum wave heights is limited to less than 40% and 60% of the reef flat water depth, respectively. As with significant wave height, both the shape and energy level of the reef flat spectra are strongly affected by changes in reef flat water depth. For higher tide levels the spectra on the reef flat closely mimic the corresponding incident spectra. However, the attenuation is greater for both lower frequencies and higher-energy portions of the spectra. This causes the reef flat spectra to be broader than those measured windward of the reef. At lower water levels, considerable energy losses due to wave breaking and bottom friction occur. Most of the energy loss comes from the vicinity of the spectral peak, and energy shifts to harmonics of the peak of the spectrum can be seen.
BACKGROUND: Since the introduction of the first atypical antipsychotics in the early 1990s, this class of medication has been increasingly relied upon for the treatment of a variety of patients with psychotic and mood disorders.DATA SOURCES: The following retrospective review was derived from the MEDLINE database using the search terms metabolic syndrome, insulin resistance, obesity, diabetes, severe mental illness, schizophrenia, bipolar disorder, mood disorders, depression, unipolar depression, and prevalence from 1966 to the present. LITERATURE SYNTHESIS: Coincident with the growing usage of these agents, there have been a growing number of literature reports of changes in metabolic homeostasis among patients taking these medications. These changes have led to interest in evaluating whether there is a relationship among these mental illnesses, their psychiatric treatments, and certain physical comorbidities known collectively as the metabolic syndrome. This article reviews the existing literature around the metabolic syndrome in patients with severe mental illnesses. CONCLUSION: Patients with severe mental illnesses, particularly schizophrenia and chronic mood disorders, demonstrate a higher prevalence of metabolic syndrome or its components compared with the general population. Based upon this increased risk in these patients, baseline and periodic medical evaluations should become a standard component in ongoing clinical assessment.
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