Chemical Diabetes Research Articles

1719-P: Plasma Glucose Response to Oral Dexamethasone Predicts Incident Prediabetes in Normoglycemic Offspring of Parents with Type 2 Diabetes

Background: Dexamethasone (dex) challenge was used historically to diagnose chemical diabetes. Here we determined its utility in predicting prediabetes in a biracial cohort. Methods: We studied 190 euglycemic subjects with parental type 2 diabetes. After a baseline 75-gram OGTT, subjects ingested 2 mg dex at 10 PM and returned at 8AM for measurement of plasma cortisol and glucose. Subjects were followed quarterly for incident prediabetes for 5 years. Serial assessments included OGTT, insulin secretion (IVGTT), and insulin sensitivity (euglycemic clamp). Results: Table 1 shows baseline characteristics and response to dex. Progressors to prediabetes had a higher glycemic response to dex than nonprogressors (<0.0001). In a regression model, post-dex fasting glucose level remained a significant predictor of Incident prediabetes after controlling for age, weight, waist, and baseline glucose (P<0.001). From ROC analysis, fasting plasma glucose ≥110 mg/dL after dex predicted incident prediabetes with 80% sensitivity and 60% specificity. Conclusion: Glycemic response to 2mg dex predicts incident prediabetes and could be useful for stratification and selection of high-risk subjects for lifestyle intervention. Table 1: Baseline demographic and glucoregulatory characteristics of subjects who developed prediabetes compared to those who remained normoglycemic. Disclosure E. Nyenwe: None. N.A. Umekwe: None. D.J. James: None. F. Ariganjoye: None. J.Y. Wan: None. S. Dagogo-Jack: Board Member; Self; Jana Care Inc. Consultant; Self; Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Sanofi-Aventis. Research Support; Self; AstraZeneca, Novo Nordisk Inc. Stock/Shareholder; Self; Dance Biopharm Holdings Inc. Funding American Diabetes Association (7-07-MN-13 to S.D-J.); National Institutes of Health

¿CUÁNTO TIENE LA PREDIABETES DE PRE-DIABETES?

Desde hace más de medio siglo los niveles glucémicos situados entre valores normales y aquellos que permiten diagnosticar diabetes mellitus han recibido nombres cambiantes. En este sentido, a fines de la década de 1950 Conn y Fajans hablaron de diabetes química y diabetes latente, dejando el término prediabetes para aquellos individuos con glucemias en todo normales pero que tenían antecedentes familiares y/o algún otro factor de riesgo para desarrollar diabetes mellitus. En 1965, el Comité de Expertos de la OMSrecomendó el uso del término “borderline diabetes”, y en 1979 el National Diabetes Data Group definió la categoría de tolerancia alterada a la glucosa (“impaired glucose tolerance”, IGT o TAG), incorporada un año después en la clasificación de la OMS.

Bone Marrow Homing Enriches Stem Cells Responsible for Neogenesis of Insulin-Producing Cells, While Radiation Decreases Homing Efficiency.

Small-sized adult bone marrow cells isolated by counterflow centrifugal elutriation and depleted of lineage markers (Fr25lin(-)) have the capacity to differentiate into insulin-producing cells and stabilize glycemic control. This study assessed competitive migration of syngeneic stem cells to the bone marrow and islets in a murine model of chemical diabetes. VLA-4 is expressed in ∼ 25% of these cells, whereas CXCR4 is not detected, however, it is transcriptionally upregulated (6-fold). The possibility to enrich stem cells by a bone marrow homing (BM-H) functional assay was assessed in sequential transplants. Fr25lin(-) cells labeled with PKH26 were grafted into primary myeloablated recipients, and mitotically quiescent Fr25lin(-)PKH(bright) cells were sorted from the bone marrow after 2 days. The contribution of bone marrow-homed stem cells was remarkably higher in secondary recipients compared to freshly elutriated cells. The therapeutic efficacy was further increased by omission of irradiation in the secondary recipients, showing a 25-fold enrichment of islet-reconstituting cells by the bone marrow homing assay. Donor cells identified by the green fluorescent protein (GFP) and a genomic marker in sex-mismatched transplants upregulated PDX-1 and produced proinsulin, affirming the capacity of BM-H cells to convert in the injured islets. There was no evidence of transcriptional priming of freshly elutriated subsets to express PDX-1, insulin, and other markers of endocrine progenitors, indicating that the bone marrow harbors stem cells with versatile differentiation capacity. Affinity to the bone marrow can be used to enrich stem cells for pancreatic regeneration, and reciprocally, conditioning reduces the competitive incorporation in the injured islets.

Two Distinct Mechanisms Mediate the Involvement of Bone Marrow Cells in Islet Remodeling: Neogenesis of Insulin-Producing Cells and Support of Islet Recovery

We have recently reported that small-sized bone marrow cells (BMCs) isolated by counterflow centrifugal elutriation and depleted of lineage markers (Fr25lin(-)) have the capacity to differentiate and contribute to regeneration of injured islets. In this study, we assess some of the characteristics of these cells compared to elutriated hematopoietic progenitors (R/O) and whole BMCs in a murine model of streptozotocin-induced chemical diabetes. The GFP(bright)CD45(+) progeny of whole BMCs and R/O progenitors progressively infiltrate the pancreas with evolution of donor chimerism; are found at islet perimeter, vascular, and ductal walls; and have a modest impact on islet recovery from injury. In contrast, Fr25lin(-) cells incorporate in the islets, convert to GFP(dim)CD45(-)PDX-1(+) phenotypes, produce proinsulin, and secrete insulin with significant contribution to stabilization of glucose homeostasis. The elutriated Fr25lin(-) cells express low levels of CD45 and are negative for SCA-1 and c-kit, as removal of cells expressing these markers did not impair conversion to produce insulin. BMCs mediate two synergistic mechanisms that contribute to islet recovery from injury: support of islet remodeling by hematopoietic cells and neogenesis of insulin-producing cells from stem cells.

Single dose streptozotocin-induced diabetes: considerations for study design in islet transplantation models.

Streptozotocin (STZ)-induced diabetes mellitus (DM) offers a very cost-effective and expeditious technique that can be used in most strains of rodents, opening the field of DM research to an array of genotypic and phenotypic options that would otherwise be inaccessible. Despite widespread use of STZ in small animal models, the data available concerning drug preparation, dosing and administration, time to onset and severity of DM, and any resulting moribundity and mortality are often limited and inconsistent. Because of this, investigators inexperienced with STZ-induced diabetes may find it difficult to precisely design new studies with this potentially toxic chemical and account for the severity of DM it is capable of inducing. Until a better option becomes available, attempts need to be made to address shortcomings with current STZ-induced DM models. In this paper we review the literature and provide data from our pancreatic islet transplantation experiments using single high-dose STZ-induced DM in NCr athymic nude mice with hopes of providing clarification for study design, suggesting refinements to the process, and developing a more humane process of chemical diabetes induction.

Elutriated Stem Cells Derived from the Adult Bone Marrow Differentiate into Insulin-Producing Cells In Vivo and Reverse Chemical Diabetes

An ongoing debate surrounds the existence of stem cells in the adult endowed with capacity to differentiate into multiple lineages. We examined the possibility that adult bone marrow cells participate in recovery from chemical diabetes through neogenesis of insulin-producing cells. Small-sized cells negative for lineage markers derived by counterflow centrifugal elutriation from the bone marrow were transplanted into mice made diabetic with streptozotocin and sublethal irradiation. These cells homed efficiently to the injured islets and contributed to tissue revascularization. Islet-homed CD45-negative donor cells identified by sex chromosomes downregulated GFP, expressed PDX-1 and proinsulin, and converted the hormone precursor to insulin. An estimated 7.6% contribution of newly formed insulin-producing cells to islet cellularity increased serum insulin and stabilized glycemic control starting at 5 weeks post-transplant and persisting for 20 weeks. Newly differentiated cells displayed normal diploid genotype and there was no evidence of fusion between the grafted stem cells or their myeloid progeny and injured β-cells. Considering the extensive functional incorporation of insulin-producing donor cells in the injured islets, we conclude that the adult bone marrow contains a subset of small cells endowed with plastic developmental capacity.

Recovery of Endogenous β-Cell Function in Nonhuman Primates After Chemical Diabetes Induction and Islet Transplantation

OBJECTIVE—To describe the ability of nonhuman primate endocrine pancreata to reestablish endogenous insulin production after chemical β-cell destruction.RESEARCH DESIGN AND METHODS—Eleven monkeys (Macaca fascicularis) were rendered diabetic with streptozotocin. Eight diabetic monkeys received intraportal porcine islet transplantation.RESULTS—Two monkeys transplanted after 75 days of type 1 diabetes showed recovery of endogenous C-peptide production a few weeks after transplantation, concomitant with graft failure. Histological analysis of the pancreas of these monkeys showed insulin-positive cells, single or in small aggregates, scattered in the pancreas and adjacent to ducts. Interestingly, numerous CK19+ cells costained with proinsulin and PDX-1 antibodies. Furthermore, the peculiar double phenotype glucagon-positive/GLUT2+ was observed. In these monkeys as well as in all others, the original islets showed no insulin staining.CONCLUSIONS—Our data provide evidence that, in nonhuman primates, the pancreas can reestablish endogenous insulin production after chemical β-cell destruction. This seems to be a nongeneralizable event with only 2 out of 11 monkeys recovering β-cell function. In these two monkeys, younger age and islet graft behavior might have played a role in triggering endogenous β-cell recovery.

Testosterone Regulates RhoA/Rho-Kinase Signaling in Two Distinct Animal Models of Chemical Diabetes

The contractile RhoA/Rho-kinase (ROCK) signaling pathway is upregulated in penile tissue in animal models of experimental diabetes and has been proposed to contribute to diabetes-related erectile dysfunction (ED). To investigate the effect of testosterone (T) on the RhoA/ROCK signaling in diabetes. We used two distinct animal models of chemical diabetes (alloxan-induced in the rabbit and streptozotocin-induced in the rat) with or not T supplementation. The effect of diabetes and T supplementation on RhoA/ROCK signaling was evaluated as responsiveness to the selective ROCK inhibitor Y-27632 either by "in vitro" contractility study (diabetic rabbit) or "in vivo" as erectile response elicited by intracavernous injections (diabetic rats). RhoA/ROCK gene and protein expression were also analyzed. In both models, hypogonadism was observed, characterized by reduced T plasma level and androgen-dependent accessory glands atrophy. Diabetic animals showed a significant increase in responsiveness to increasing concentrations of Y-27632. T substitution (30 mg/kg, weekly) completely prevented hypogonadism and diabetes-induced penile hypersensitivity to Y-27632. To test whether this effect was due to a T-dependent regulation of RhoA/ROCK gene expression, we measured RhoA/ROCK mRNA. Both isoforms of ROCK (ROCK1/ROCK2) were analyzed by real-time reverse transcriptase polymerase chain reaction (RT-PCR) in rat penile samples. We found that ROCK1 mRNA was significantly increased (P < 0.05) in penile tissues from diabetic animals and maintained at the control values by T, as also confirmed by semiquantitative RT-PCR in rabbit. Conversely, RhoA and ROCK2 mRNA expression was not influenced either by diabetic condition or by T administration. Accordingly, ROCK1 protein expression, as evaluated by Western blot and immunohistochemistry analysis, was increased in penile samples from diabetic animals and normalized by T. Our data further support the hypothesis that the overexpression of RhoA/ROCK signaling contributes to diabetes-related ED. Moreover, treating hypogonadism in course of diabetes may maintain erectile function also by normalizing RhoA/ROCK pathway upregulation.

Effects of chemical diabetes and starvation on blood and organ carnitine concentrations in rats

Carnitine (CARN) is known for shuttling fatty acids across the mitochondrial membrane, but its role in carbohydrate (CHO) metabolism is less well defined. This study examines the effect of altered CHO metabolism on CARN status. Agestratified rats received one of the treatments in Table 1. Total CARN was measured in plasma, red blood cells (RBC), liver, heart, muscle, and epididymis. Table 1: Male and Female Carnitine Concentrations

Current status of pancreatic islet transplantation

DM (diabetes mellitus) is a metabolic disorder of either absolute or relative insulin deficiency. Optimized insulin injections remain the mainstay life-sustaining therapy for patients with T1DM (Type I DM) in 2006; however, a small subset of patients with T1DM (approx. 10%) are exquisitely sensitive to insulin and lack counter-regulatory measures, putting them at higher risk of neuroglycopenia. One alternative strategy to injected insulin therapy is pancreatic islet transplantation. Islet transplantation came of age when Paul E. Lacy successfully reversed chemical diabetes in rodent models in 1972. In a landmark study published in 2000, Shapiro et al. [A. M. Shapiro, J. R. Lakey, E. A. Ryan, G. S. Korbutt, E. Toth, G. L. Warnock, N. M. Kneteman and R. V. Rajotte (2000) N. Engl. J. Med. 343, 230-238] reported seven consecutive patients treated with islet transplants under the Edmonton protocol, all of whom maintained insulin independence out to 1 year. Substantial progress has occurred in aspects of pancreas procurement, transportation (using the oxygenated two-layer method) and in islet isolation (with controlled enzymatic perfusion and subsequent digestion in the Ricordi chamber). Clinical protocols to optimize islet survival and function post-transplantation improved dramatically with the introduction of the Edmonton protocol, but it is clear that this approach still has potential limitations. Newer pharmacotherapies and interventions designed to promote islet survival, prevent apoptosis, to promote islet growth and to protect islets in the long run from immunological injury are rapidly approaching clinical trials, and it seems likely that clinical outcomes of islet transplantation will continue to improve at the current exponential pace.

Testosterone Restores Diabetes‐Induced Erectile Dysfunction and Sildenafil Responsiveness in Two Distinct Animal Models of Chemical Diabetes

Hypogonadism is often associated with diabetes and both conditions represent major risk factors for erectile dysfunction (ED). To investigate the role of hypogonadism on phosphodiesterase type 5 (PDE5) expression and sildenafil responsiveness in diabetes. Two different models of experimental diabetes were used: (i) alloxan-induced diabetic rabbit; and (ii) streptozotocin (STZ)-induced diabetic rat. In both experimental models, animals were separated into three groups: control, diabetic, diabetic supplemented with testosterone (T) enanthate. Rabbits were used for "in vitro" experiments. Conversely, each rats group was further subdivided: no further treatment or acute sildenafil dosing (25 mg/kg, 1 hour before "in vivo" electrical stimulation [ES]). Erectile capacity was evaluated either by "in vitro" contractility study (alloxan-induced diabetic rabbit) and "in vivo" evaluation of erectile response elicited by ES of cavernous nerve (STZ-induced diabetic rats). Also endothelial nitric oxide synthase, neural nitric oxide synthase (nNOS), and PDE5 protein (Western blot) and mRNA (quantitative real-time reverse transcriptase polymerase chain reaction [RT-PCR]) expression were measured in rat penile samples of each group. In both models, hypogonadism was observed, characterized by reduced T and atrophy of androgen-dependent accessory glands. T substitution completely reverted hypogonadism and diabetes-induced penile hyposensitivity to "in vitro" (acetylcholine, rabbit) or "in vivo" (ES, rat) relaxant stimuli, along with nNOS expression, which was reduced (P < 0.05) in STZ rats. In diabetic animals, T substitution reinstated sildenafil-induced enhancement of both "in vitro" nitric oxide donor (NCX 4040) relaxant effect (rabbit) and "in vivo" ES-induced erection (rat). PDE5 was reduced in diabetic STZ rats (P < 0.05) and normalized by T. In STZ rats, sodium nitroprusside (SNP) intracavernous injection induced a more sustained erection than in control rats, which was no further enhanced by sildenafil. T substitution normalized both hyper-responsiveness to SNP and sildenafil efficacy. In two models of diabetes T deficiency underlies biochemical alterations leading to ED. Normalizing T in diabetes restores nNOS and PDE5, and reinstates sensitivity to relaxant stimuli and responsiveness to sildenafil.

Diabetes Alters Osmotic Swelling Characteristics and Membrane Conductance of Glial Cells in Rat Retina

The development of edema in the diabetic retina may be caused by vascular leakage and glial cell swelling. To determine whether diabetic retinopathy alters the swelling characteristics of retinal glial cells and changes the properties of the glial membrane K+ conductance, isolated retinas and glial cells of rats were investigated at 4 and 6 months of chemical diabetes. After 6 months of hyperglycemia, application of a hypotonic solution to retinal slices induced swelling of glial cell bodies, a response not observed in control retinas. The osmotic glial cell swelling was blocked by inhibitors of phospholipase A2 or cyclooxygenase and by a thiol-reducing agent. Glial cells from diabetic retinas displayed a decrease of K+ currents that was associated with an altered subcellular distribution of the K+ conductance and a loss of perivascular Kir4.1 protein. The observation that swelling of cells in control retinas was inducible with K+ channel-blocking Ba2+ ions suggests a relationship between decreased K+ inward currents and osmotic cell swelling in diabetic retinas. The data show that glial cells in diabetic retinas are more sensitive to osmotic stress, which is associated with a decrease of K+ currents, than cells in control retinas. It is suggested that these alterations may be implicated in the development of diabetic retinal edema.

Adoptive Transfer of Mast Cells Abolishes the Inflammatory Refractoriness to Allergen in Diabetic Rats

Mast cells are pivotal secretory cells primarily implicated in allergen-evoked inflammatory responses and are downregulated following experimental chemical diabetes. Here we tested the hypothesis that a decrease in the number and reactivity of mast cells would account for the hyporesponsiveness of diabetic rats to allergen-induced inflammation. We found that the anaphylactic release of histamine from sensitized ileum, trachea and skin tissues was clearly reduced in rats turned diabetic via intravenous administration of alloxan. Likewise, actively and passively sensitized diabetic rats mounted a weaker allergen-evoked pleural mast cell degranulation and protein extravasation, as compared to sensitized nondiabetic animals, which paralleled a marked reduction in the mast cell population in the pleural cavity. The number of mast cells enumerated in the mesentery from diabetic rats was also clearly reduced. The allergen-evoked plasma leakage in diabetic rats was restored by the transfer of mast cells from sensitized nondiabetic rats. Moreover, the adoptive transfer of sensitized mast cells from diabetics to naive animals led to a lower allergen-induced exudation as compared to the response noted after the transfer of sensitized naive mast cells. Purified mast cells from diabetic rats were hyporesponsive to antigen and compound 48/80 stimulation in vitro as attested by histamine release. Thus, our results show that the phenomenon of refractoriness of diabetic animals to allergen challenge appears to be accounted for by a reduction in the number and reactivity of mast cells.

The complex dynamics of diabetes modeled as a fractal complex-adaptive-system (FCAS)

An approach is suggested in this paper that has successfully been applied in physics, ecology, and the biomedical sciences. This is called fractal-complex-adaptive-system (FCAS) modeling. The objective of this type of analysis is to reconstruct the dynamics of the pathological process that has been leading to the disease. Diabetes, a complexdisease, has been used to test the methodology. Biometrical analyses were undertaken on subjects diagnosed with overt diabetes (hereafter called IDDM), chemical diabetes (NIDDM), and a group of normal subjects. The studied variables were plasma glucose, insulin concentration, and insulin sensitivity. FCAS modeling consists in fitting a power-law function to the bivariate lognormal distribution of the variables. The power-law exponent is estimated by principal component analysis (PCA). Analyses have shown that glucose disposal can be considered a fractal process, thereby implying a complex hierarchy of interacting scales and mechanisms in glucose handling. The first principal component represents quantitative glucose disposal, and the second component is compatible with insulin efficiency. PCA further retrieved distinct ongoing pathological processes within clinical groups of subjects. The IDDM insulin production defect had a high (absolute value) exponent of -3.5 that confirms a crude defect scanning the whole fractal hierarchy. Definite insulin resistance has been detected in clinically normal subjects with a low exponent of -0.5, thus suggesting a subtle and complex problem possibly due to aging or reduced physical activity. Insulin sensitivity was definitely impaired in the NIDDM clinical group with an exponent of -2.2, thereby suggesting poorly scheduled insulin feedback, possibly due to peripheral insensitivity. NIDDM appeared to result from aggravation of the subtle insensitivity seen in normal subjects. On the whole, the fractal model seemed to be capable of assessing the degree of complexity of a disease. It is concluded that future studies of diabetes using FCAS modeling ought to be undertaken on the basis of multiple-scale biological variables, thereby closely reflecting the complexity of glucose handling. It is further recommended that such analyses be undertaken with dynamic data to track down the precise timing of the various homeostatic disruptions. It would also be important to carry out this type of analysis on less known but equally complex disease processes. The results might point to important new research findings.

Reduced insulin, GLUT2, and IDX-1 in beta-cells after partial pancreatectomy.

Reduction of GLUT2 is associated with loss of glucose-induced insulin secretion in genetic and chemical diabetes and in transplanted islets exposed to chronic hyperglycemia. To examine the mechanisms for this loss of GLUT2 in normal islets exposed to hyperglycemia, we performed studies on Sprague Dawley rats 4 weeks after a 90% partial pancreatectomy (Px), a well-characterized model of hyperglycemia. GLUT2 immunofluorescence in the beta-cell of Px rats was greatly reduced. Western blot analysis of homogenates of isolated Px islets also showed a reduction in GLUT2 protein; densitometry measurements were 36 +/- 3% of values from islets of sham-operated controls. Insulin protein levels were decreased to a similar extent. Islet GLUT2 and insulin mRNA were measured with quantitative reverse transcriptase-polymerase chain reaction. The level of GLUT2 mRNA from Px islets was 24 +/- 4% of that of islets from sham-operated controls; similar results were obtained for insulin. Because both these beta-cell-specific messages were reduced, we analyzed the Px islets for the pancreas-duodenum-specific transcription factor IDX-1(IPF-1, STF-1, PDX-1) protein. It was markedly reduced (approximately 80%) in islets from the Px rats. These data suggest that 1) the loss of GLUT2 protein associated with hyperglycemia is at least partially explained by reduced levels of the GLUT2 gene transcripts; 2) the reduction of beta-cell insulin content during chronic hyperglycemia may not be completely due to degranulation (reduced levels of gene transcripts may play a role); and 3) the reduction in the transcription factor IDX-1 raises the possibility that dysregulation of transcription factors may contribute to the abnormal beta-cell function found in states of chronic hyperglycemia.

Stability Over Time of Modern Diagnostic Criteria for Type II Diabetes

To examine the long-term stability of the World Health Organization criteria for diabetes in the 8-yr follow-up of the San Antonio Heart Study. A problem with older criteria for diagnosing diabetes was that many individuals classified as having borderline or chemical diabetes reverted to nondiabetic status on follow-up. Few studies have addressed this issue among diabetic patients who meet the more stringent, modern National Diabetes Data Group or World Health Organization criteria. We studied 98 Mexican-American and 44 non-Hispanic white type II diabetic patients 8 yr after they were diagnosed according to World Health Organization criteria in a population-based epidemiological survey. Patients were classified as follows: whether they were on pharmacological treatment for diabetes at baseline, or, if not, whether they had a prior diagnosis of diabetes at the time of their baseline survey visit or were newly diagnosed. Of the 142 patients who met the study criteria for type II diabetes at baseline and whose status at follow-up was known, 20 (14.1%; 95% confidence interval 9.0-20.5%) no longer met criteria at follow-up 8 yr later. All but 2 of those who reverted to nondiabetic status were from the newly diagnosed group. Two of 20 had lost more than 5.0 kg over the 8 yr and an additional 5 had lost 2.5-5.0 kg. The 20 patients who reverted to nondiabetic status lacked many of the associated anthropometric, physiological, and metabolic findings of diabetes such as obesity, unfavorable body fat distribution, and dyslipidemia. Moreover, only one had proteinuria, and none had any grade of diabetic retinopathy at baseline. Epidemiological surveys that rely on a single oral glucose tolerance test to determine the prevalence of type II diabetes may overestimate prevalence by as much as 16% (95% confidence interval 10.5-23.6%) (142/122 = 1.16). The actual overestimate could well be less because some patients who truly have diabetes at baseline may be in remission at follow-up as a result of significant weight loss. Despite these difficulties, the modern National Diabetes Data Group and World Health Organization criteria are more stable than earlier criteria.

Induction of alloxan/streptozotocin diabetes in dogs: a revised experimental technique.

The diabetic dog represents an excellent model for use in many aspects of diabetic research. The present paper describes, in detail, a reproducible experimental protocol for the successful induction of chemical diabetes in beagles using a combination of the 2 pancreatic beta-cell cytoxic agents alloxan and streptozotocin.

ENDOCRINE FUNCTION IN PATIENTS WITH THAIASSHMIA MAJOR

Endocrine function was investigated in 44(22 female, 22 male) transfusion dependent and deferoxamine treated thalassemic patients between 2.9 and 21.3 years(mean: 10.9 yrs) of age. Pretransfusion hemoglobin ranged from 6.5 to 9.2 g/dl and serum ferritin from 375 to 11000 ng/ml. 17 patients were growth retarded and 25 of 38 patients had delayed bone age. Of the 16 patients (11F, 5M) over 13 years of age, 14 had delayed puberty (in onset or progression). Hypoparathyroidism was present in two patients and diabetes in one patient. All patients had normal basal serum T4 and cortisol levels. Basal serum TSH was elevated in one subject. TSH response to TRH was exaggerated in 7 of 21 patients. GH response to stimulation (insulin and L-dopa) was subnormal in 4 of 20 cases. While 13 of 16 patients had decreased cortisol response to hypoglycemia, only 1 of 6 patients had decreased response to ACTH. Three of 9 patients over 13 years and with delayed puberty had no LH, FSH response to GHRH. Oral GTT showed chemical diabetes in one of 8 cases. The results suggest that endocrine abnormalities are common in patients with thalassemia major treated with frequent transfusion and chelating therapy.

Liver fatty acid composition in the spontaneously diabetic BB rat

The purpose of the present experiment was to investigate if the modulation by insulin of liver microsomal desaturase activities in the spontaneously diabetic adult male Bio-Breeding (BB) rat, with destructive insulitis resembling the lesions described in the human Type I (insulin-dependent) diabetes, corresponds to modifications in fatty acid composition, reflect of changes in fatty acid desaturation. We observed no significant differences between BB rats, during the hyper-(48 h), the normo-(17 h) and the hypo-glycemic (3 h) periods which followed the insulin injection, and control rats for the fatty acid composition of liver total lipids, phosphatidylethanolamines, phosphatidylcholines, triacylglycerols, cholesterol esters and non esterified fatty acids. On the other hand, linoleic acid of BB rats liver phospholipids increased, comparatively to control rats, while arachidonic acid decreased, in agreement with previously reported results on chemical diabetes and consistent with a defective delta 6 desaturation, particularly during the normo-and hyper-glycemic periods, and the fact that control of membrane lipid composition is multifactorial.

Familial hypercatabolic hypoproteinemia. A disorder of endogenous catabolism of albumin and immunoglobulin.

The metabolism of albumin and IgG was investigated in two siblings, products of a first-cousin marriage, a female aged 34 yr and a male aged 17, who had a marked reduction in their respective serum concentrations of IgG (1.3 and 3.1 mg/ml) and albumin (19 and 21 mg/ml). The metabolism of radioiodinated IgG and albumin was studied in the two patients. The total circulating and body pools of IgG were less than 28% of normal. The IgG synthetic rates were within the normal range. However, the IgG survival was short, with their respective fractional catabolic rates increased fivefold to 31% and 36% of the intravenous pool per day (normal, 6.7 +/- 2%/d). Furthermore, the patients had reduced total body pools, normal synthetic rates, and increased fractional catabolic rates for albumin. There was no proteinuria or abnormality of renal or liver function. In addition, the patients did not have circulating antibodies directed toward IgG, IgA, or albumin. Furthermore, both patients had normal fecal 51Cr-labeled albumin tests, thus excluding excessive gastrointestinal protein loss. We propose that these siblings have a previously unrecognized familial disorder characterized by reduced serum concentrations of IgG and albumin caused by a defect in endogenous catabolism, leading to a short survival of these proteins that is associated in this family with chemical diabetes and a skeletal deformity.