Alan C. Moses

Bio: Alan C. Moses is an academic researcher from Beth Israel Deaconess Medical Center. The author has contributed to research in topics: Insulin & Thyroid. The author has an hindex of 22, co-authored 36 publications receiving 2432 citations. Previous affiliations of Alan C. Moses include Joslin Diabetes Center.

Recombinant Human Insulin-Like Growth Factor I Increases Insulin Sensitivity and Improves Glycemic Control in Type II Diabetes

Abstract: Insulin resistance is a major factor in the pathophysiology of type II diabetes and a major impediment to successful therapy. The identification of treatments that specifically target insulin resistance could improve diabetes management significantly. Since IGFs exert insulin-like actions and increase insulin sensitivity when administered at supraphysiological doses, we determined the effect of 6 weeks of recombinant human IGF-I (rhIGF-I) administration on insulin resistance and glycemic control in obese insulin-resistant patients with type II diabetes. A total of 12 patients with type II diabetes were recruited for the study. Subcutaneous administration of rhIGF-I (100 micrograms/kg b.i.d.) significantly lowered blood glucose. Fructosamine declined from 369 to 299 mumol/l by 3 weeks of administration and then declined further to 271 at the end of 5 weeks. Glycosylated hemoglobin, which was 10.4% pretreatment, declined to 8.1% at the end of therapy. Mean 24-h blood glucose during a modal day was 14.71 +/- 4.5 mmol/l pretreatment and declined to 9.1 +/- 3.21 mmol/l by the end of treatment. These improvements in glycemia were associated with a decrease in serum insulin levels. Mean insulin concentrations declined from 108.0 to 57.0 pmol/l during the modal day measurements and from 97.2 to 72.0 pmol/l during the mixed-meal tolerance test. Changes in glycemia were accompanied by a marked increase in insulin sensitivity. The insulin sensitivity index (SI) calculated from a frequently sampled intravenous glucose tolerance test (FSIVGTT) after the method of Bergman et al. (Bergman RN, Finegold DT, Ader M: Assessment of insulin sensitivity in vivo. Endocr Rev 6:45-86, 1985) increased 3.4-fold. Furthermore, the improvement in glycemic control was accompanied by a change in body composition with a 2.1% loss in body fat as calculated by dual energy x-ray absorptiometry without change in total body weight. Significant side effects were present in some subjects, although nine subjects were able to complete at least 4.5 weeks of the protocol and six subjects completed the entire 6 weeks. Supraphysiological IGF-I concentrations were maintained throughout the study, increasing from 206 micrograms/l in the control period to 849 micrograms/l at the end of 6 weeks of rhIGF-I treatment. The increase in IGF-I levels was accompanied by a significant increase in IGF binding protein-2 levels, a slight reduction in IGF binding protein-3 levels, and an increase in levels of IGF binding protein-1. In summary, IGF-I significantly lowered blood glucose as reflected by short-term and long-term indexes of glycemic control and increased insulin sensitivity. It remains to be determined whether a dosage can be administered that avoids significant side effects and still achieves reasonable glycemic control.

Differential Cardiac Effects of Growth Hormone and Insulin-like Growth Factor1 in the Rat A Combined In Vivo and In Vitro Evaluation

Abstract: Background Despite their increasing clinical use and recent evidence that growth hormone (GH) and insulin-like growth factor–1 (IGF-1) target the heart, there has been no systematic investigation of the effects of GH and IGF-1 on the cardiovascular system. Methods and Results Sixty normal but growing adult female rats were randomized to receive 4 weeks of treatment with GH (3.5 mg · kg−1 · d−1), IGF-1 (3 mg · kg−1 · d−1), a combination of the two, or placebo. Transthoracic echocardiograms were performed at baseline and at 2 weeks and 4 weeks of treatment. After the final echocardiography, rats underwent either closed-chest left ventricular (LV) catheterization or Langendorff perfusion studies. Myocyte diameter and interstitial tissue fraction were assessed by morphometric histology. Echocardiographic and ex vivo data demonstrated a LV hypertrophic response in all three groups of treated animals that was most marked in the GH group, which alone exhibited a concentric growth pattern (relative wall thickness...

Serum CTX: a new marker of bone resorption that shows treatment effect more often than other markers because of low coefficient of variability and large changes with bisphosphonate therapy.

Abstract: Serum CrossLaps is a new assay for measuring carboxy-terminal collagen crosslinks (CTX) in serum. This measurement is reported to be more specific to bone resorption than other measurements. However, the utility of this and other markers in monitoring patients on antiresorptive therapy depends on how often changes anticipated with therapy exceed changes attributable to random variability. In a study where subjects received either placebo or pamidronate, we calculated the minimum significant change (MSC), that is, the change that was sufficiently large that it was unlikely to be due to spontaneous variability. We also examined the changes in markers of bone turnover in subjects treated with pamidronate (APD) (30 mg I.V. in 500 ml D5W over 4 hours) to see how often observed changes in turnover after treatment exceeded the MSC. The MSC for serum CTX was 30.2%, and was significantly (P < 0.05) lower than the MSC for urinary NTX (54.0%), and not significantly different from the MSC of urinary DPD (20.6%). Ninety percent of subjects treated with APD had a decline in serum CTX that exceeded the MSC, compared with 74% for bone-specific alkaline phophatase (BSAP), 57% for urinary N-telopeptide cross-links (NTX), and 48% for free deoxypyridinoline. Changes in serum CTX correlated reasonably well with changes in spine BMD after 2 years (r = 0.47), but this correlation did not quite reach statistical significance because of the small number of subjects. In conclusion, the serum CTX assay shows greater utility for assessing efficacy of antiresorptive treatment than some previously described markers.

Insulin-like growth factor-1 but not growth hormone augments mammalian myocardial contractility by sensitizing the myofilament to Ca2+ through a wortmannin-sensitive pathway: studies in rat and ferret isolated muscles

Abstract: A growing body of evidence has been accumulated recently suggesting that growth hormone (GH) and insulin-like growth factor-1 (IGF-1) affect cardiac function, but their mechanism(s) of action is unclear. In the present study, GH and IGF-1 were administered to isolated isovolumic aequorin-loaded rat whole hearts and ferret papillary muscles. Although GH had no effect on the indices of cardiac function, IGF-1 increased isovolumic developed pressure by 24% above baseline. The aequorin transients were abbreviated and demonstrated decreased amplitude. The positive inotropic effects of IGF-1 were not associated with increased intracellular Ca2+ availability to the contractile machinery but to a significant increase of myofilament Ca2+ sensitivity. Accordingly, the Ca2+-force relationship obtained under steady-state conditions in tetanized muscle was shifted significantly to the left (EC50, 0.44+/-0.02 versus 0.52+/-0.03 micromol/L with and without IGF-1 in the perfusate, respectively; P<0.05); maximal Ca2+-activated tetanic pressure was increased significantly by 12% (211+/-3 versus 235+/-2 mm Hg in controls and IGF-1-treated hearts, respectively; P<0.01). The positive inotropic actions of IGF-1 were not associated with changes in either pHi or high-energy phosphate content, as assessed by 31P nuclear magnetic resonance spectroscopy, and were blocked by the phosphatidylinositol 3-kinase inhibitor wortmannin. Concomitant administration of IGF binding protein-3 blocked IGF-1-positive inotropic action in ferret papillary muscles. In conclusion, IGF-1 is an endogenous peptide that through a wortmannin-sensitive pathway displays distinct positive inotropic properties by sensitizing the myofilaments to Ca2+ without increasing myocyte [Ca2+]i.

The combination of insulin-like growth factor I and insulin-like growth factor-binding protein-3 reduces insulin requirements in insulin-dependent type 1 diabetes: evidence for in vivo biological activity.

Abstract: Insulin-like growth factor-I (IGF-I) enhances insulin action in normal subjects and in patients with both type 1 and 2 diabetes; however, its administration is associated with significant side effects in a high percentage of patients. The coadministration of IGF binding protein-3 (IGFBP-3, the predominant IGF binding protein in serum) with IGF-I limits IGF-I inducible side effects, but it does not attenuate the ability of IGF-I to enhance protein synthesis and bone accretion; therefore, we determined whether IGF-I/IGFBP-3 would retain biological activity in type 1 DM and limit side effects associated with free IGF-I administration. Twelve patients received recombinant human IGF-I plus IGFBP-3 (2 mg/kg-day) by continuous sc infusion for 2 weeks. Each subject served as his own control; and, during a paired 2-week period, each received a placebo infusion. The order of the treatments was randomized. Subjects were placed on a constant caloric intake but were allowed to adjust insulin doses to maintain appropriate levels of glycemic control. Subjects measured blood glucose four times per day at home and kept a log of their insulin use. Frequent sampling for glucose, insulin, and GH was conducted during four inpatient study periods, one at the beginning and one at the end of each 2-week study interval. During IGF-I/IGFBP-3, insulin doses were reduced by 49%, and mean serum glucose was reduced by 23%. Free insulin levels obtained during frequent sampling in hospital fell 47% on IGF-I/IGFBP-3, compared with control, but showed no change with placebo. Concomitant glucose measurements did not differ in the two treatment groups. There was no change in body weight. Fructosamine levels decreased by 12%, but this was not significant (P < 0.1). Fasting triglyceride was unchanged, but cholesterol declined from 170 +/- 24 to 149 +/- 31 mg/dL (P < 0.05). IGFBP-2 (an IGF-I-dependent responsive variable) rose from 141 +/- 56 to 251 +/- 98 ng/mL (P < 0.01) on IGF-I/IGFBP-3. To analyze the mechanism by which IGF-I/IGFBP-3 might reduce insulin requirements, the change in serum GH was quantified. Mean GH levels were reduced by 72%, from 2.48 to 0.55 ng/mL (P < 0.001). An equal number (40%) of drug- and placebo-treated subjects had minor hypoglycemic episodes at home that required adjustment of insulin doses. No episode was classified as severe. In contrast to previous studies with free IGF-I, there were no cases of edema, headache, jaw pain, retinal edema, or Bell's palsy. No subject withdrew because of drug complications. These findings indicate that IGF-I/IGFBP-3 is biologically active on carbohydrate metabolism, as measured by a decrease in insulin requirements in patients with type 1 diabetes. Further studies will be required to determine the long-term safety and efficacy of this combination in patients with insulin resistance and diabetes.

A Serious Adverse Event after Successful Gene Therapy for X-Linked Severe Combined Immunodeficiency

Abstract: To the Editor: We recently reported (April 18 issue)1 the sustained correction of X-linked severe combined immunodeficiency disease by ex vivo, retrovirally mediated transfer of the γc gene into CD34+ cells in four of five patients with the disease. These results have since been confirmed in four additional patients with typical X-linked severe combined immunodeficiency. Of the first four successfully treated patients, three continue to do well up to 3.6 years after gene therapy, whereas a serious adverse event occurred in the fourth patient. At a routine checkup 30 months after gene therapy, lymphocytosis consisting of a monoclonal population . . .

Physiological and molecular basis of thyroid hormone action.

Abstract: Thyroid hormones (THs) play critical roles in the differentiation, growth, metabolism, and physiological function of virtually all tissues. TH binds to receptors that are ligand-regulatable transcription factors belonging to the nuclear hormone receptor superfamily. Tremendous progress has been made recently in our understanding of the molecular mechanisms that underlie TH action. In this review, we present the major advances in our knowledge of the molecular mechanisms of TH action and their implications for TH action in specific tissues, resistance to thyroid hormone syndrome, and genetically engineered mouse models.

Paracrine Mechanisms in Adult Stem Cell Signaling and Therapy

Abstract: Animal and preliminary human studies of adult cell therapy following acute myocardial infarction have shown an overall improvement of cardiac function. Myocardial and vascular regeneration have been initially proposed as mechanisms of stem cell action. However, in many cases, the frequency of stem cell engraftment and the number of newly generated cardiomyocytes and vascular cells, either by transdifferentiation or cell fusion, appear too low to explain the significant cardiac improvement described. Accordingly, we and others have advanced an alternative hypothesis: the transplanted stem cells release soluble factors that, acting in a paracrine fashion, contribute to cardiac repair and regeneration. Indeed, cytokines and growth factors can induce cytoprotection and neovascularization. It has also been postulated that paracrine factors may mediate endogenous regeneration via activation of resident cardiac stem cells. Furthermore, cardiac remodeling, contractility, and metabolism may also be influenced in a paracrine fashion. This article reviews the potential paracrine mechanisms involved in adult stem cell signaling and therapy.