Diagnosis and management of type 2 diabetes in adults: a review of the ICSI guideline.

Diabetes is a complex chronic disease that affects approximately 25% of people above the age of 60 in the United States. This poses a significant challenge to primary care physicians to provide optimal treatment plans to improve metabolic control and to minimize debilitating complications. This article provides a summary of the recent guideline published by the Institute for Clinical Systems Improvement (ICSI) for the Diagnosis and Management of Type 2 Diabetes Mellitus in Adults. The purpose of this guideline is to provide a comprehensive approach to the diagnosis and management of prediabetes and type 2 diabetes in adults. Management strategies from the evidence-based guideline will include recommendations for nutrition therapy, physical activity, self-management approaches, and pharmacologic agents.

Influence of age on the association of retinol-binding protein 4 with metabolic syndrome.

OBJECTIVE: The relationships of retinol-binding protein 4 (RBP4) with insulin sensitivity and body fat distribution have been investigated in a few recent studies with conflicting results. This may have been due to differences in ages of the subjects in the different studies. The aim of this study was to investigate whether the association of RBP4 and insulin sensitivity and percent trunk fat are influenced by age. METHODS AND PROCEDURES: Cross-sectional analyses of 48 young subjects and 55 elderly subjects. Insulin sensitivity was determined by a hyperinsulinemic-euglycemic clamp. Body fat distribution was determined by a dual-energy X-ray absorptiometry (DXA). RESULTS: In the young subjects, RBP4 levels were associated with insulin sensitivity (r = -0.30, P = 0.04), percent trunk fat (r = 0.54, P < 0.001), triglycerides (r = 0.44, P = 0.003), low-density lipoprotein (r = 0.38, P = 0.01). In contrast, in the elderly subjects there was no correlation between RBP4 levels and insulin sensitivity (r = -0.18, P = 0.20), percent trunk fat (r = 0.00, P = 0.10), triglycerides (r = 0.25, P = 0.10), and low-density lipoprotein (r = -0.11, P = 0.47). DISCUSSION: The associations of RBP4 with insulin sensitivity, percent trunk fat, and lipid levels are influenced by age.

Limb fat to trunk fat ratio in elderly persons is a strong determinant of insulin resistance and adiponectin levels.

BACKGROUND: Similar to lipodystrophy syndromes, aging results in increased visceral adiposity with loss of subcutaneous adipose tissue in the extremities. The hypothesis of this study is that the distribution of limb fat to trunk fat (LF/TF) ratio in elderly persons has a stronger correlation than trunk fat alone to insulin resistance and adiponectin levels. METHODS: Thirty-eight elderly participants were divided into an insulin-resistant (IR) group and an insulin-sensitive (IS) group. Limb fat and trunk fat were measured by dual-energy x-ray absorptiometry. Insulin resistance was measured by a hyperinsulinemic-euglycemic clamp. RESULTS: There was no significant difference between the IS and IR groups with respect to body mass index, body fat index, absolute amount of trunk fat, or percent body fat. However, the difference in LF/TF ratio between the IS (1.02 +/- 0.05) and the IR groups (0.77 +/- 0.05) was highly significantly different (p <.001). Insulin resistance had a stronger correlation to the LF/TF ratio (r = 0.61, p <.001) than to absolute trunk fat (r = -0.32, p =.051). Adiponectin levels had a strong association with the LF/TF ratio (r = 0.63, p <.001), but did not correlate to absolute trunk fat (r = -0.24, p =.18). CONCLUSIONS: The distribution of body fat (LF/TF ratio) in elderly persons is a stronger determinant of insulin resistance and adiponectin levels than is trunk fat alone. The LF/TF ratio can be a useful tool to assess insulin sensitivity in the elderly population.

Wall suction applied to needle muscle biopsy - a novel technique for increasing sample size.

BACKGROUND: The needle biopsy technique described by Bergström is the most commonly used technique to obtain samples to assess muscle metabolism. Sampling of muscle, particularly the vastus lateralis, has become an essential tool in biomedical and clinical research. Optimal sample size is critical for availability of tissue for processing. To evaluate the effectiveness of a novel technique to obtain adequate sample size using wall suction applied to needle muscle biopsy, we collected samples from subjects in on-going clinical studies for gene expression. MATERIALS AND METHODS: Muscle biopsy samples of the vastus lateralis using 6 mm Bergström needles under local anesthesia were obtained from 55 subjects who had volunteered to participate in this research project. The vastus lateralis was biopsied according to the methods described by Bergström with a 6 mm biopsy needle. Wall suction was applied to the inner bore of the biopsy needle after the needle was inserted into the muscle. RESULTS: The mean sample of biopsy taken using the 6 mm was 233 mg (n = 55). The wall suction (200 mm Hg) applied to the needle pulled the surrounding tissue into the central bore of the needle. The quality of the samples was adequate for all biochemical assays. The biopsy technique did not result in any complications due to infection or bleeding. CONCLUSIONS: Using a novel technique of connecting a 6 mm Bergström biopsy needle to wall suction, we have obtained 200 to 300 mg muscle biopsy specimens uniformly, with ease, and minimal discomfort. An increase in sample size allows for a wider variety of biochemical and histopathological analysis.

Insulin-like growth factor-I provokes functional antagonism and internalization of beta1-adrenergic receptors.

Hormones that activate receptor tyrosine kinases have been shown to regulate G protein-coupled receptors, and herein we investigate the ability of IGF-I to regulate the beta(1)-adrenergic receptor. Treating Chinese hamster ovary cells in culture with IGF-I is shown to functionally antagonize the ability of expressed beta(1)-adrenergic receptors to accumulate intracellular cAMP in response to stimulation by the beta-adrenergic agonist Iso. The attenuation of beta(1)-adrenergic action was accompanied by internalization of beta(1)-adrenergic receptors in response to IGF-I. Inhibiting either phosphatidylinositol 3-kinase or the serine/threonine protein kinase Akt blocks the ability of IGF-I to antagonize and to internalize beta(1)-adrenergic receptors. Mutation of one potential Akt substrate site Ser412Ala, but not another Ser312Ala, of the beta(1)-adrenergic receptor abolishes the ability of IGF-I to functionally antagonize and to sequester the beta(1)-adrenergic receptor. We also tested the ability of IGF-I to regulate beta(1)-adrenergic receptors and their signaling in adult canine cardiac myocytes. IGF-I attenuates the ability of beta(1)-adrenergic receptors to accumulate intracellular cAMP in response to Iso and promotes internalization of beta(1)-adrenergic receptors in these cardiac myocytes.

Retinol-binding protein 4 is associated with insulin resistance and body fat distribution in nonobese subjects without type 2 diabetes.

BACKGROUND: Adipose tissue is responsible for releasing various adipokines that have been related to insulin resistance. Understanding the relationship of these adipokines to insulin resistance may foster the development of new treatments for diabetes. OBJECTIVES: The primary objective of this study was to determine whether an association between retinol-binding protein 4 (RBP4) and insulin resistance exists in nonobese individuals without a family history or diagnosis of diabetes. The secondary objective was to determine by a dual energy x-ray absorptiometry scan which adipose tissue depot most closely relates to RBP4 levels. DESIGN: Cross-sectional analysis of 92 study participants ranging in age from 20 to 83 yr was performed. The range of body mass index (BMI) was from 18 to 30 kg/m(2). Exclusion criteria were a BMI greater than 30 kg/m(2), family history of diabetes, or a diagnosis of diabetes. Insulin sensitivity was determined by a hyperinsulinemic euglycemic clamp. Body fat was measured by dual energy x-ray absorptiometry scan. RESULTS: RBP4 values were lower in females (35.8 +/- 1.7 microg/ml) compared with males (39.9 +/- 1.4 microg/ml; P = 0.06). RBP4 levels were found to correlate negatively with insulin sensitivity (r = -0.32; P = 0.002) and positively with age (r = 0.38; P < 0.001). RBP4 levels did not correlate with BMI (r = -0.13; P = 0.22), trunk fat (r = 0.16; P = 0.22), or percent body fat (r = 0.07; P = 0.65). However, RBP4 levels did correlate with percent trunk fat (r = 0.36; P = 0.001). CONCLUSION: These findings indicate a relationship between RBP4, insulin sensitivity, and percent trunk fat in individuals who may not have features of insulin resistance.

G-protein-coupled receptors and tyrosine kinases: crossroads in cell signaling and regulation.

G-protein-coupled receptors and protein tyrosine kinases represent two prominent pathways for cellular signaling. As our knowledge of cell signaling pathways mediated by the superfamily of G-protein-coupled receptors and the smaller family of receptor tyrosine kinases expands, so does our appreciation of how these two major signaling platforms share information and modulate each other, otherwise termed "cross-talk". Cross-talk between G-protein-coupled receptors and tyrosine kinases can occur at several levels, including the receptor-to-receptor level, and at crucial downstream points (e.g. phosphatidylinositol-3-kinase, Akt/protein kinase B and the mitogen-activated protein kinase cascade). Regulation of G-protein-coupled receptors by non-receptor tyrosine kinases, such as Src family members, also operates in signaling. A broader understanding of how G-protein-coupled receptors and tyrosine kinases cross-talk reveals new insights into signaling modalities in both health and disease.

Successful expression of a functional yeast G-protein-coupled receptor (Ste2) in mammalian cells.

G-protein-coupled receptors (GPCRs) are membrane-embedded cell signaling devices transducing ligand binding to activation of heterotrimeric G-proteins, providing a paradigm for signaling for yeast and mammals alike. Probing the extent to which yeast GPCRs may couple to mammalian G-proteins has been problematic. In the current work, we explored conditions that enable the cell-surface expression of a yeast alpha-factor pheromone receptor (Ste2). When expressed in human HEK293 cells, Ste2 is shown to bind its ligand alpha-factor, to be functional and catalyze activation of the mitogen-activated protein kinase cascade, and to demonstrate agonist-induced internalization. In response to agonist Ste2 as maintained intracellularly for several hours and avoids the degradation process observed for Ste2 in yeast cells. This is the first successful demonstration of the ability to express a functional yeast GPCR in mammalian cells.

The 15-amino acid motif of the C terminus of the beta2-adrenergic receptor is sufficient to confer insulin-stimulated counterregulation to the beta1-adrenergic receptor.

Insulin counterregulates catecholamine action in part by inducing the sequestration of beta2-adrenergic receptors. Although similar to agonist-induced sequestration, insulin-induced internalization of beta2-adrenergic receptors operates through a distinct and better-understood cellular pathway. The effects of insulin treatment on the function and trafficking of both beta1- and beta2-adrenergic receptors were tested. The beta2-adrenergic receptors were counterregulated and internalized in response to insulin. The beta1-adrenergic receptors, in sharp contrast, are shown to be resistant to the ability of insulin to counterregulate function and induce receptor internalization. Using chimeric receptors composed of beta1-/beta2-adrenergic receptors in tandem with mutagenesis, we explored the role of the C-terminal cytoplasmic tail of the beta2-adrenergic receptors for insulin-induced counterregulation. Substitution of the C-terminal cytoplasmic tail of the beta2-adrenergic receptor on the beta1-adrenergic receptor enabled the chimeric G protein-coupled receptor to be functionally and spatially regulated by insulin. Truncation of the beta2-adrenergic receptor C-terminal cytoplasmic tail to a 15-amino acid motif harboring a potential Src homology 2-binding domain at Y350 and an Akt phosphorylation site at S345,346 was sufficient to enable receptor regulation by insulin.

Probing receptor structure/function with chimeric G-protein-coupled receptors.

Owing its name to an image borrowed from Greek mythology, a chimera is seen to represent a new entity created as a composite from existing creatures or, in this case, molecules. Making use of various combinations of three basic domains of the receptors (i.e., exofacial, transmembrane, and cytoplasmic segments) that couple agonist binding into activation of effectors through heterotrimeric G-proteins, molecular pharmacology has probed the basic organization, structure/function relationships of this superfamily of heptahelical receptors. Chimeric G-protein-coupled receptors obviate the need for a particular agonist ligand when the ligand is resistant to purification or, in the case of orphan receptors, is not known. Chimeric receptors created from distant members of the heptahelical receptors enable new strategies in understanding how these receptors transduce agonist binding into receptor activation and may be able to offer insights into the evolution of G-protein-coupled receptors from yeast to humans.

Adverse events due to discontinuations in drug use and dose changes in patients transferred between acute and long-term care facilities.

BACKGROUND: Care transitions are commonplace for ill older adults, but no studies to our knowledge have examined the occurrence of iatrogenic harm from medication changes during patient transfer. OBJECTIVES: To identify medication changes during transfer between hospital and nursing home and adverse drug events (ADEs) caused by these changes. METHODS: Participants were residents of 4 nursing homes in the New York City metropolitan area admitted to 2 academic hospitals. Nursing home and hospital medical records were reviewed to identify changes in medication regimens between sites. Medications were matched and compared regarding dosage, route, and frequency of administration. Two physician investigators used structured implicit review to identify ADEs attributable to transfer-related medication changes. RESULTS: During a total of 122 admissions, the mean numbers of medications altered during transfer from nursing home to hospital and hospital to nursing home were 3.1 and 1.4, respectively (P<.001 for comparison). Most changes in drug use were discontinuations, followed by dose changes and class substitutions. Of 71 bidirectional transfers that were reviewed by 2 physician investigators, ADEs attributable to medication changes occurred during 14 (20%). The overall risk of ADE per drug alteration (n = 320) was 4.4% (95% confidence interval, 2.5%-7.4%). Although most medication changes (8/14) implicated in causing ADEs occurred in the hospital, most ADEs (12/14) occurred in the nursing home after nursing home readmission. CONCLUSIONS: Medication changes are common during transfer between hospital and nursing home and are a cause of ADEs. Research is needed on interinstitutional patient care and systems interventions designed to prevent ADEs.

Trafficking of beta2-adrenergic receptors: insulin and beta-agonists regulate internalization by distinct cytoskeletal pathways.

Insulin and beta-adrenergic agonists stimulate a rapid phosphorylation and sequestration of the beta2-adrenergic receptors (beta2ARs). Although the expectation was that a common pathway would be involved in the trafficking of the beta2AR in response to either hormone, studies reported herein show the existence of unique cytoskeletal requirements for internalization/recycling of G-protein-coupled receptors, such as the beta2AR. Treatment of human epidermoid carcinoma A431 cells with nocodazole, which binds tubulin monomer in vivo and catalyzes the depolymerization of microtubules, effectively blocks beta-adrenergic agonist-induced, but not insulin-induced, sequestration of beta2ARs. Treatment with latrunculin-A, an agent that sequesters actin monomer and leads to loss of actin filaments, had no effect on the ability of beta-adrenergic agonists to stimulate internalization of beta2ARs, but blocked the ability of insulin to stimulate counterregulation of beta2ARs via internalization. Although nocodazole had no effect on insulin-stimulated sequestration of beta2ARs, the recycling of the internalized receptors to the cell membrane was sensitive to depolymerization of microtubules by this agent. Latrunculin-A, by contrast, blocks the recycling of beta2ARs internalized in response to beta-agonist, while attenuating recycling of receptors internalized in response to insulin stimulation. These data show the existence of unique cytoskeletal requirements for G-protein-coupled-receptor trafficking in response to agonist compared with a counterregulatory hormone, and for sequestration versus recycling of the receptors to the cell membrane.