Faculty Bibliography

Diabetes evolves through prediabetes, defined as impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT). Subjects with IFG/IGT have an increased risk of developing diabetes and a higher prevalence of cardiovascular disease than normoglycemic individuals. However, there is considerable evidence that glucose levels lower than those meeting the current definition of prediabetes may also be associated with similar concerns, particularly in high-risk individuals in accordance with a continuous glycemic risk perspective. Therefore, an absolute definition of prediabetes may underestimate the implications and vastness of this disorder. Research should focus on these aspects to minimize the risk of developing a preventable condition

Prediabetes comprising Impaired Fasting Glucose (IFG) and Impaired Glucose Tolerance (IGT) represents an intermediate stage of altered glucose metabolism between normal glucose levels and type 2 diabetes mellitus and is associated with an increased risk for the development of diabetes and cardiovascular disease. There is considerable evidence that glucose levels lower than those meeting the current definition of prediabetes may also be associated with similar risks particularly in high-risk individuals. Prediabetes is often unrecognized and therefore constitutes a major public health concern suggesting the need for earlier intervention than is currently recommended.

PURPOSE. To compare the efficacy and safety of pravastatin, gemfibrozil, combined therapy, and placebo in the treatment of hypercholesterolemia. PATIENTS AND METHODS: At 5 centers in Sweden and 2 in Finland, 290 ambulatory patients were randomized to active treatment or placebo for 12 weeks following a single-blind placebo lead-in period. The study was double-blind and placebo-controlled. Patients had plasma total cholesterol levels of at least 6.0 mmol/L or in the 90th percentile by age and sex and triglycerides less than 4.0 mmol/L. Concentrations of lipids, lipoproteins, and apolipoproteins were measured, and clinical laboratory tests included liver function and creatine kinase determinations. RESULTS: Pravastatin reduced total cholesterol (26.3% versus 15.2%, p less-than-or-equal-to 0.01), low-density lipoprotein cholesterol (LDL-C) (33.5% versus 16.8%, p less-than-or-equal-to 0.01), and apolipoprotein B (28.8% versus 15.3%, p less-than-or-equal-to 0.01) more than gemfibrozil. Gemfibrozil reduced very-low-density lipoprotein cholesterol (VLDL-C) (49.1% versus 21.9%, p less-than-or-equal-to 0.01) and triglycerides (42.2% versus 14.2%, p less-than-or-equal-to 0.01) and increased high-density lipoprotein cholesterol (HDL-C) (15.2% versus 5.9%, p less-than-or-equal-to 0.01) more than pravastatin. Pravastatin and gemfibrozil increased apolipoprotein A-I comparably (3.3% versus 5.0%, p = NS). The combination significantly (p less-than-or-equal-to 0.01) reduced total cholesterol (29.0%), LDL-C (37.1%), VLDL-C (49.4%), and apolipoprotein B (31.6%), and increased HDL-C (16.8%). The combination reduced the total cholesterol/HDL-C (39.3%) and LDL-C/HDL-C (45.8%) ratios significantly (p < 0.01). Adverse events and clinical laboratory abnormalities were generally mild and transient in all groups, although creatine kinase tended to be higher with combination therapy. Study drugs were withdrawn from two patients with asymptomatic creatine kinase elevations. Severe myopathy was not observed, however, the presence of subclinical musculoskeletal effects cannot be excluded. CONCLUSIONS: Co-administration of pravastatin and gemfibrozil combined the specific effects of the two drugs on lipoprotein concentrations and ratios. The incidence of side effects was low; severe myopathy did not occur. The combination may be useful in selected cases of combined hyperlipidemia; however, since myopathy at a low incidence or after long-term therapy cannot be excluded, the routine use of combination therapy is not advisable.

Using a tissue culture system based on a nearly pure population of avian precartilage mesenchymal cells, we have found that ambient glucose levels as little as 50% lower, or 100% higher, than normally present in embryonic sera are deleterious to cartilage development, as measured by the accumulation of highly sulfated proteoglycan and the corresponding cartilage-specific chondroitin sulfate core protein mRNA. Abnormal glucose concentrations in the ranges studied did not selectively influence cell replication, and the effects on chondrogenesis were not due to differences in overall protein synthesis or glucose utilization in the treatment groups. Core protein gene expression was more severely affected than accumulation of extracellular product, suggesting the existence of posttranscriptional compensatory mechanisms. The sensitivity to ambient glucose levels of both expression of the cartilage-specific chondroitin sulfate core protein gene and the accumulation of the corresponding extracellular matrix macromolecules during chondrogenesis suggest a molecular mechanism for the well-known adverse effect of maternal diabetes on embryonic skeletogenesis. The results further suggest that hypoglycemia resulting from stringent control of diabetes may also be deleterious to skeletal development