Gregg D. Simonson

Diagnosis of insulin resistance and associated syndromes : the spectrum from the metabolic syndrome to type 2 diabetes mellitus

Insulin resistance is a common underlying physiologic abnormality associated with central obesity, type 2 diabetes and cardiovascular disease. Clinically, its hallmark markers of hypertension, glucose intolerance and dyslipidemia have been grouped into associated syndromes of insulin resistance. Insulin resistance is now considered a useful marker of clinical risk and a target for therapeutic intervention. While the criteria for diagnosis of syndromes related to insulin resistance have been established, the clinical diagnosis of insulin resistance remains a significant challenge. As more clinicians focus on the management of insulin resistance in patients with cardiovascular disease, type 2 diabetes and other syndromes of insulin resistance, its diagnosis will take on increasing importance. This review focuses on the current definition and diagnosis of insulin resistance and associated syndromes.

Genomic organization and promoter sequence of a gene encoding a rat liver-specific type-1 transport protein

Abstract We report the isolation and characterization of a rat gene (designated TI-LTP ) encoding a liver-specific cell-surface glycoprotein that belongs to the type-I transporter family. This gene, including 5′ and 3′ flanking domains, was cloned from a rat λDASH genomic library and its nucleotide sequence was determined. TI-LTP is a single-copy gene which spans over 6 kb and contains nine introns ranging in size from 90 bp to over 1.8 kb. Two transcription start points were located using a nuclease S-1 protection assay. The TI-LTP promoter (pTI-LTP) lacks a canonical TATA-box element, but does contain five TAGA elements. Several putative transcription-factor-binding sites were identified in the pTI-LTP , including activator protein 2 (AP-2) sites and a peroxisome proliferator response element ( PPRE ).

Undetected, uncontrolled blood pressure in type 2 diabetes: self‐monitored blood pressure profiles

Objectives: To construct a novel and clinically relevant means of representing self‐monitored blood pressure (SMBP). Methods: Patients treated to an office blood pressure (BP) <130/80 mmHg measured their BP at home for 14 days using an Omron IC® semi‐automatic portable monitor with memory. SMBP data were transferred from the monitor to a computer to produce graphic profiles (SMBPp) that depict the hourly variation in BP throughout a “typical” or modal day. Results: Office BP and SMBP data from 66 subjects with type 2 diabetes and hypertension (HTN), who completed a previous study of intensified management, were analyzed based on European Society of Hypertension‐European Society of Cardiology (ESH‐ESC) classifications. Patients were classified as Optimal (6), Normal (12), High Normal (15), Isolated systolic HTN (29) and Grades 1, 2 or 3 HTN (4). SMBP disagreed in 32 cases, placing 29 patients in higher risk categories. Analysis by SMBPp of the 33 patients originally classified as Optimal, Normal or High Normal showed that on average 50 ± 31% of their systolic SMBP values exceeded ESH‐ESC thresholds for HTN (135 mmHg). It also revealed that 74 ± 21% of their SMBP values exceeded the treatment goal (<125 mmHg) for high‐risk patients with type 2 diabetes. Conclusions: SMBPp allowed for a definitive measurement of the dynamic daily BP changes. It produced compelling evidence of persistent patterns of BP fluctuations among patients with normal office BP whose uncontrolled HTN would have remained undetected.

Different actions of peroxisome proliferator-activated receptors: molecular mechanisms and clinical importance

Purpose of reviewLigands that bind to peroxisome proliferator-activated receptors (PPARs) have been shown to modify lipid metabolism and reduce insulin resistance – a common underlying physiologic abnormality associated with central obesity, type 2 diabetes, and cardiovascular disease. This review focuses on the different molecular mechanisms of PPARs, and potential metabolic and clinical benefits. Recent findingsTo date, three subtypes of PPARs (PPARα, PPARδ, and PPARγ) have been identified. Activation of PPARα by fibrates and polyunsaturated fatty acids alters lipid metabolism, resulting in an increase in high-density lipoprotein cholesterol and reduction of triglycerides. Activation of PPARγ by thiazolidinediones decreases peripheral insulin resistance, yielding beneficial antihyperglycemic properties. This class has also been shown to play a key role in the regulation of adipose tissue differentiation and proliferation. Both PPARα and PPARγ reduce levels of inflammatory markers, including cytokines and metalloproteinases. Dual PPAR agonists (glitazar class) are currently undergoing clinical studies to determine whether activation of both PPARα and PPARγ results in additive effects on lipid metabolism, insulin sensitivity and inflammation. PPARδ appears to be a regulator of lipid metabolism, increasing fatty acid oxidation in muscle and adipose tissue and reducing adiposity. The clinical benefit of PPARδ has yet to be established. SummaryActivation of cell signaling pathways regulated by PPARs alters lipid and glucose metabolism, as well as lowering insulin resistance. The potential metabolic and clinical benefits of PPAR activation continue to be demonstrated in clinical studies, making this an area of intense research focus for years to come.

Type 1 Diabetes

Type 1 diabetes is a disorder characterized by abnormally high blood sugar levels. In this form of diabetes, specialized cells in the pancreas called beta cells stop producing insulin. Insulin controls how much glucose (a type of sugar) is passed from the blood into cells for conversion to energy. Lack of insulin results in the inability to use glucose for energy or to control the amount of sugar in the blood.