Missing Hormone Research Articles

C-Peptide is Relevant in Type 1 Diabetes and its Complications: Summary and Conclusions to the Special Issue

It has been very satisfying to put together this Special Edition of The Review of Diabetic Studies on C-peptide and diabetes. We are greatly encouraged by the advances being made in this research area, and especially to see the beneficial effects of C-peptide making their way into clinic. Once regarded as a redundant waste product of insulin synthesis, C-peptide is now recognized as an important regulatory hormone in its own right. Our understanding of C-peptide physiology is expanding rapidly. It is abundantly clear that C-peptide deficiency in type 1 diabetes plays important pathogenetic roles in the development of various complications, with consequent beneficial effects upon C-peptide replacement. Over the last decade and a half, a wealth of new information has accumulated regarding C-peptide's interaction with a variety of cell types, its intracellular signaling mechanisms, and its impact on specific cell functions, as well as growth and cell death. It also emerges from these reviews that several questions remain, e.g. the conundrum of C-peptide's interaction with the cell membrane remains unresolved. Is there a C-peptide receptor which, to date, has escaped detection? It is clear that C-peptide binds to cell membranes and accumulates in endosomes in the cytoplasm. Also, it exerts effects on major signaling pathways such as the MAPK and PI-3 kinase pathways with fundamental influences on Na+/K+-ATPase and eNOS acivities. These activities affect renal, peripheral nerve, and vascular functions. Another effect of C-peptide is the regulation of a variety of transcription factors, with impacts on gene and protein expression of structural and functional proteins in the central and peripheral nervous systems, and in renal tissues. Such effects have led to the suggestion that C-peptide may interact with insulin-signaling activities, which in certain cell-systems can be abolished with Wortmannin, but not in others. There is also evidence showing that C-peptide exerts its cellular signaling via a G-protein-coupled receptor, since its signal can be abolished in the presence of pertussis toxin. Interestingly, some of the pepide's activities are operative in the absence of insulin, as in red blood cells and rheological functions. Instead, C-peptide seems to exert such effects by binding to Zn2+-ions, suggesting a charge-specific interaction. Recent observations demonstrate that the peptide is capable of disaggregating insulin hexamers. This effect may be important in relation to exocytosis of insulin from the beta-cells. One of the transcription factors regulated by C-peptide is NF-κB with downstream effects on inflammatory properties in the vasculature and the central nervous system. Such effects occur in the absence of any effect on hyperglycemia. Perturbations of several transcription factors influence oxidative stress and apoptotic activities. Hence, C-peptide exerts anti-inflammatory and anti-apoptotic effects in several target tissues of type 1 diabetes complications. The major thrust of the research activities regarding C-peptide physiology has concerned its effects on microvascular complications of type 1 diabetes. In the type 2 diabetic situation, C-peptide effects have not yet been fully explored. Thus, elevated levels of C-peptide may possibly have adverse effects on atherogenesis and on red blood cell ATP synthesis with downstream effects on platelet and endothelial functions. On the other hand, reports also show that C-peptide is capable of preventing intimal hyperplasia and occlusion of vascular grafts. The beneficial effects of C-peptide on the chronic complications in type 1 diabetic patients have been repeatedly documented with respect to microvascular circulation, as well as renal and peripheral nerve complications. The mechanisms underlying these beneficial effects appear to vary in different tissues, and insulin is not always necessary for C-peptide to function. Furthermore, the physiological effects of C-peptide are conveyed within a narrow concentration range. Based on present knowledge, we can envisage that replacement of C-peptide, the second missing hormone in type 1 diabetes, may have a major impact in the prevention and treatment of the dreaded complications of diabetes. Proof of concept has been demonstrated. The principle of replacement therapy is not new, but is the basic rationale for the treatment of a number of endocrinological disorders. There are compelling reasons to call for responsible national agencies, patient interest groups, and the pharmaceutical industry to engage, and to promote large scale clinical trials. This would provide an early opportunity for the increasing type 1 diabetes population to benefit soon from therapy with this peptide. Disclosures: The authors report no conflict of interests.

Effects of OnceVersusTwice-Daily Parathyroid Hormone 1–34 Therapy in Children with Hypoparathyroidism

Hypoparathyroidism is among the few hormonal insufficiency states not treated with replacement of the missing hormone. Long-term conventional therapy with vitamin D and analogs may lead to nephrocalcinosis and renal insufficiency. Our objective was to compare the response of once-daily vs. twice-daily PTH 1-34 treatment in children with hypoparathyroidism. The study was conducted at a clinical research center. Fourteen children ages 4-17 yr with chronic hypoparathyroidism were studied. This was a randomized cross-over trial, lasting 28 wk, which compared two dose regimens, once-daily vs. twice-daily PTH1-34. Each 14-wk study arm was divided into a 2-wk inpatient dose-adjustment phase and a 12-wk outpatient phase. Mean predose serum calcium was maintained at levels just below the normal range. Repeated serum measures over a 24-h period showed that twice-daily PTH 1-34 increased serum calcium and magnesium levels more effectively than a once-daily dose. This was especially evident during the second half of the day (12-24 h). PTH 1-34 normalized mean 24-h urine calcium excretion on both treatment schedules. This was achieved with half the PTH 1-34 dose during the twice-daily regimen compared with the once-daily regimen (twice-daily, 25 +/-15 microg/d vs. once-daily, 58 +/- 28 microg/d; P < 0.001). We conclude that a twice-daily PTH 1-34 regimen provides a more effective treatment of hypoparathyroidism compared with once-daily treatment because it reduces the variation in serum calcium levels and accomplishes this at a lower total daily PTH 1-34 dose. The results showed, as in the previous study of adult patients with hypoparathyroidism, that a twice-daily regimen produced significantly improved metabolic control compared with once-daily PTH 1-34.

Use (or misuse) of vitamin D treatment in CKD and dialysis patients: A recent meta-analysis on vitamin D compounds in chronic kidney disease [1] and an editorial comment [2] accompanying this meta-analysis have already been published. We believe that these papers deserve some comments in the interest of the NDT readership

1,25-Dihydroxy vitamin D (vitamin D) is a hormone with a number of pharmacological and physiological effects, first demonstrated as the effect to cure osteomalacia and later as a hormone with effects related to mineral homeostasis, cell differentiation, immunology, vascular calcification and ageing [3–5]. The hormone, 1,25-dihydroxy vitamin D, is formed from cholecalciferol, that is 25-hydroxylated in the liver and 1-α-hydroxylated in the kidney. In addition 1-αhydroxylase activity has been demonstrated in a number of cells outside the kidney. The activity of the extrarenal 1-αhydroxylase is, however, not enough to keep physiological plasma levels of 1,25-dihydroxy vitamin D, and the renal 1-α-hydroxylase activity is therefore of utmost importance for maintaining a normal physiological homeostasis. In patients with chronic uraemia, reduced kidney mass and low kidney function, the renal 1-α-hydroxylase activity is clearly reduced, as demonstrated by the very low levels of plasma 1,25-dihydroxy vitamin D found in a number of studies on patients with chronic kidney disease (CKD). When dealing with administration of vitamin D compounds in patients with CKD on or not yet on dialysis, one clearly has to distinguish between the goal of providing the patients with substitution of the missing hormone or providing the patients a pharmacological effect of vitamin D. Concerning the substitution of physiological levels of 1,25-dihydroxy vitamin D in patients with CKD, it is obvious that not many studies in a randomized controlled way have compared the effect of substitution to the effect of severe hormone depletion in patients with CKD. That is similar to the situation in other endocrine and severe hormonedepleted diseases. As such, one will not be able to find good randomized controlled studies that are comparing untreated Addison with cortisone-treated patients, or patients with severe type 1 DM treated with or without insulin. Therefore, when looking at the physiological effects of hormones, we do accept that such effects exist, despite the

Androgen therapy in the aging male.

The world population is expanding rapidly; at the same time, life expectancy is increasing, and fertility rates are decreasing. Due to these facts, it is expected that the biggest increases of population growth will occur in the aging population. In the aging male, endocrine changes and a decline in endocrine function involve tissue responsiveness as well as reduced secretory output from peripheral glands and alterations in the central mechanism controlling the temporal organization of hormonal release. The latter are likely to be responsible for the dampened circadian hormonal and non-hormonal rhythms. These are in part responsible for the age-dependent decrease of the peripheral levels of testosterone, dehydroepiandrosterone (DHEA), the thyroid hormones, growth hormone (GH), IGF1 and melatonin. These hormonal changes, which develop in most men at about the age of 50, are in part responsible for endocrine deficiencies of some older men. One of the best-studied endocrine deficiencies is late-onset hypogonadism. This is a syndrome characterized by adverse effects on multiple organ systems and decreased quality of life, associated with advancing age and characterized by signs and symptoms of hypogonadism and a deficiency in serum androgen levels with or without a decreased genomic sensitivity to androgens. In cases of endocrine deficiencies, traditional endocrinology aims to replace the missing hormone or hormones with substitutes. It has been demonstrated that interventions such as hormone therapies may favorably influence some of the pathological conditions in aging men by preventing the preventable and delaying the inevitable. A comprehensive medical, psycho-social and life-style history, a physical examination and laboratory testing are essential for the diagnosis and management of late-onset hypogonadism. Acute, chronic or inter-current diseases must be taken into consideration prior to initiating any hormonal substitution therapy. In the era of evidence-based medicine, we have to acknowledge that data on testosterone therapy (HT) in the aging male is mostly circumstantial, based on experience in the treatment of transitional or chronic hypogonadism in young men resulting from disease or experiments of nature. However, over the past several years prospective studies on testosterone therapy in the aging male were performed and shown to be beneficial for certain older men in preventing or delaying some aspects of aging. Recommendations for algorithms for the diagnosis of late-onset hypogonadism and monitoring therapy for safety and efficacy are the subject of this paper.

Use and indication of vitamin D and vitamin D analogues in patients with renal bone disease.

Vitamin D plays a pivotal role in the pathogenesis and treatment of renal bone disease. Vitamin D levels decline in the early phase of renal failure, however, through a compensatory mechanism parathyroid hormone (PTH) stimulates the production of 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3), calcitriol) to return it to normal circulating concentrations. Nevertheless, resistance to calcitriol is observed and may be related to the decreased presence of the heterodimeric, DNA-binding partner for the vitamin D receptor protein. In end-stage kidney disease (ESKD) the circulating levels of calcitriol are invariably low. The indications of vitamin D therapy are the replacement of the missing hormone vs suppression of hyperparathyroidism (HPT) requiring daily low-dose oral vs intermittent 'pulse' or oral administration. However, this therapy must be accompanied by careful patient monitoring to avoid hypercalcaemia and low bone turnover. Low bone turnover is not merely a histologic entity, but a clinical condition associated with a high risk of extraosseous calcifications, in particular in the cardiovascular system, leading to increased morbidity. Thus, determination of bone turnover in patients with ESKD is essential. Bone biopsy is the gold standard to assess bone turnover, however, it is not always available and nephrologists rely on PTH levels. The intact PTH assay measures PTH(1-84) and large C-PTH fragments, which may antagonize the PTH(1-84) effects on bone. An assay that measures exclusively PTH(1-84) has recently become available and a calculated PTH(1-84)/C-PTH fragment ratio has been shown to be the best predictor of bone turnover in patients with ESKD not treated with vitamin D or with other medications known to affect bone metabolism. 1,25-dihydroxy-22-oxavitamin D(3) (22-oxacalcitriol, OCT) is a vitamin D analogue that could control serum PTH concentrations without deleterious effects on bone.

Use and indication of vitamin D and vitamin D analogues in patients with renal bone disease

Vitamin D plays a pivotal role in the pathogenesis and treatment of renal bone disease. Vitamin D levels decline in the early phase of renal failure; however, through a compensatory mechanism parathyroid hormone (PTH) stimulates the production of calcitriol to return it to normal circulating concentrations. Nevertheless, resistance to calcitriol is observed and may be related to the decreased presence of the heterodimeric, DNA-binding partner for the vitamin D receptor protein. In end-stage kidney disease (ESKD) the circulating levels of calcitriol are invariably low. The indications of vitamin D therapy are the replacement of the missing hormone versus suppression of hyperparathyroidism requiring daily low-dose oral versus intermittent pulse or oral administration. However, this therapy must be accompanied by careful patient monitoring to avoid hypercalcemia and low bone turnover. Low bone turnover is not merely a histologic entity, but a clinical condition associated with high risk of extraosseous calcifications, in particular in the cardiovascular system, leading to increased morbidity. Thus, determination of bone turnover in patients with ESKD is essential. Bone biopsy is the gold standard to assess bone turnover, however, it is not always available and nephrologists rely on PTH levels. The intact PTH assay measures PTH (1-84) and large C-PTH fragments, which may antagonize the PTH (1-84) effects on bone. An assay that measures exclusively PTH (1-84) has recently become available and a calculated PTH (1-84) /C-PTH fragment ratio has been shown to be the best predictor of bone turnover in patients with ESKD not treated with vitamin D or with other medications known to affect bone metabolism. 22-Oxacalcitriol is a vitamin D analogue that could control serum PTH concentrations without deleterious effects on bone.

Well-being, mood and calcium homeostasis in patients with hypoparathyroidism receiving standard treatment with calcium and vitamin D.

Standard treatment in hypoparathyroidism consists of calcium and vitamin D (or vitamin D analogs) but does not employ replacement of the actual missing hormone. Only few studies have evaluated the efficacy of calcium/vitamin D treatment in hypoparathyroidism; the impact of chronic hypoparathyroid disease on well-being has not been investigated previously. Cross-sectional, controlled study in 25 unselected women with postsurgical hypoparathyroidism since 6.4plus minus8.0 years (s.d.) on stable treatment with calcium and vitamin D (or analogs) and in 25 controls with a history of thyroid surgery but intact parathyroid function, who were matched for sex, age and time since surgery. Assessment of well-being and mood using validated questionnaires (the revised version Symptom Checklist 90 (SCL-90-R); the Giessen Complaint List (GBB-24); and the von Zerssen Symptom List (B-L Zerssen)), serum and urinary calcium/phosphorus homeostasis, and in the hypoparathyroid patients also screening for secondary disease by kidney ultrasound, ophthalmological split lamp examination, and measurement of bone mineral density. Serum calcium was in the accepted therapeutic range in the majority of hypoparathyroid patients. However, calcium/phosphorus homeostasis as a whole was clearly non-physiological. Nephrolithiasis was detected in 2 and cataracts in 11 of 25 hypoparathyroid patients. As compared with controls, hypoparathyroid patients had significantly higher global complaint scores in GBB-24 (P=0.036), B-L Zerssen (P=0.002) and SCL-90-R (P=0.020) with predominant increases in the subscale scores for anxiety, phobic anxiety and their physical equivalents. Current standard treatment in hypoparathyroidism is not only associated with an altered calcium/phosphorus homeostasis but also fails to restore well-being in these patients. Future studies need to address the impact of more physiological treatment options like parathyroid hormone(1-34) or parathyroid transplantation on well-being and mood in these patients.

Utilisation des cellules des îlots de Langerhans en thérapie cellulaire

Insulin dependent diabetes mellitus is a common disease affecting 1.5 million patients in Europe. It is currently treated by multiple injections of insulin associated with blood glucose self monitoring. The goal of the treatment is to obtain near normal glucose concentration, in order to prevent the later complications (retinopathy, nephropathy, neuropathy, macroangiopathy) of the disease--which may be severe--while avoiding severe hypoglycaemia. Although diabetes therapy has improved enormously in the last few decades, intensive research is currently aimed at replacing not only the missing hormone but also the cells which normally produce insulin in the pancreas. Transplantation of insulin secreting cells as a treatment of diabetes mellitus therefore has a special significance among other applications of cell therapy, since it deals with a disease which already has an efficient therapy. The aim of this article is the discussion of the objectives and the hopes in this field.

A rational approach to short stature: focus on use and abuse of growth hormone.

The abundant supply of recombinant growth hormone has raised interesting possibilities of several new applications. While supplementation of the missing hormone in patients with growth hormone deficiency is still the undisputed primary indication for its use, there is now convincing evidence of its usefulness in the therapy of short stature due to Turner syndrome and pre-transplant chronic renal failure in childhood. Numerous studies on patients with other causes of short stature have failed to show any significant benefit in final adult height. Social pressures notwithstanding, it is still premature to advocate the use of this expensive therapy for indications other than the three stated above especially since our understanding of potential long-term complications from such treatment is far from complete.

The Insulin‐dependent Patient: Perceptions and Preferences

Although patients realize that insulin is the missing hormone which keeps them alive and well, they do not regard it as a cure for diabetes because it may cause hypoglycaemia, it does not completely abolish the risk of long-term side-effects, and it does not permit a life-style equivalent to their prediabetic state. Clearly, though, insulin can improve quality of life and significantly reduce the risk of complications. Patients' perceptions of their illness and the available treatment have been explored by several means: letters written to a diabetes specialist nurse by children with diabetes, group discussion at a Young Adult Clinic and responses to questions at the annual Youth Diabetes Conference. Improvements in patient care will stem from physicians' awareness of patients' perceptions and from developments in insulin therapy.

Characterization and metabolic regulation of a liver-specific 5.4-kilobase mRNA whose synthesis is transcriptionally induced by carbohydrates and repressed by glucagon and cyclic AMP.

Four clones derived from a carbohydrate-induced rat liver cDNA library were found to hybridize with a 5.4-kilobase mRNA species encoding a 36 kDa protein. This mRNA was abundant in the liver, barely detectable in adipocytes and kidney, and absent from the other tissues tested. In the liver, the mRNA was fully induced by a carbohydrate-rich diet, but was undetectable during both starvation and feeding with a protein-rich or lipid-rich diet. Adrenalectomized, thyroidectomized and diabetic animals did not express the mRNA in their liver when re-fed with the carbohydrate-rich diet. When these animals were given the missing hormone, the amount of hybridizable RNA returned to normal values, but administration of the hormone alone failed to induce mRNA synthesis in starved animals. Both glucagon and its second messenger, cyclic AMP, abolished the induction of the mRNA in re-fed animals. Exogenous insulin, whatever the dose, did not reverse the inhibitory action of glucagon. In an isolated nuclei transcription system, no detectable RNA transcripts were found in starved animals, whereas feeding the animals with the carbohydrate-rich diet led to a maximum rate of gene transcription. Although unidentified, this mRNA proves to be a remarkable marker of dietary and hormonal control of gene expression in vivo. It will provide a useful model for further analysis of the role of cyclic AMP in regulating the transcription of eukaryotic genes.

In vivo hormonal control of L-type pyruvate kinase gene expression. Effects of glucagon, cyclic AMP, insulin, cortisone, and thyroid hormones on the dietary induction of mRNAs in the liver.

Using a cDNA probe complementary to rat L-type pyruvate kinase mRNAs, we studied the respective roles of glucocorticoids, thyroid hormones, glucagon, and insulin in the induction of specific mRNAs in the liver of animals refed either a maltose-rich or a fructose-rich diet. Neither adrenalectomized nor thyroidectomized nor diabetic animals could express L-type pyruvate kinase mRNAs in their liver when refed the carbohydrate-rich diets. When the animals were given the missing hormone, the level of hybridizable mRNAs returned to normal values but administration of the hormone alone failed to induce mRNA synthesis in fasted animals. Both glucagon and cyclic AMP abolished the induction of L-type pyruvate kinase mRNAs in refed animals. Exogenous insulin, whatever the dose, could not reverse the inhibitory action of glucagon. Insulin has usually been regarded as the main regulator of L-type pyruvate kinase gene expression. It appears now that glucagon, beside regulating the enzyme activity by phosphorylation mechanisms, may also modulate L-type pyruvate kinase synthesis at a pre-translational level. Consequently, our results show that three conditions are required for the synthesis of liver L-type pyruvate kinase mRNAs: (i) the presence of dietary carbohydrates, (ii) the cessation of glucagon release, and (iii) the presence of permissive hormones, including insulin.

Minor Hemoglobins, Diabetic "Control," and Diseases of Postsynthetic Protein Modification

Editorials1 October 1977Minor Hemoglobins, Diabetic "Control," and Diseases of Postsynthetic Protein ModificationCHARLES M. PETERSON, M.D., F.A.C.P., ROBERT L. JONES, M.D.CHARLES M. PETERSON, M.D., F.A.C.P.Search for more papers by this author, ROBERT L. JONES, M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-87-4-489 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptAlthough diabetes mellitus has been recognized as a clinical syndrome since the Ebers Papyrus, and the ideal therapy has been available in the form of replacement of the missing hormone since the 1920s, the disease continues to challenge the clinician through its almost ubiquitous sequelae. Hyperglycemia and ketosis are generally accepted as being the direct result of insulin deficiency. The causes of other sequelae are not as clear; complications often arise during long periods of time and may be due to insulinopenia, hyperglycemia, or other factors acting alone or in concert.With the advent of radioimmunoassays, measurements of hormone reserve...

Amphibian metamorphosis: The role of thyrotropin-like hormone

The role of the pituitary hormones in tadpole growth and differentiation is still incompletely understood. Well-characterized antisera to specific mammalian hormones create essentially single hormone deficits and allow analysis of the role of the missing hormone in specified processes. The effect of thyrotropin antiserum administered to prometamorphic Rana catesbeiana tadpoles during thyroxine (T 4)-induced or spontaneous metamorphosis has been studied. Compared to control animals treated with normal rabbit serum, thyrotropin antiserum depressed the rate of hind limb growth during T 4-induced metamorphosis to about 50% of the response to T 4 alone and completely blocked hind limb growth during spontaneous metamorphosis. These observations support the conclusions that (1) a thyrotropin-like hormone is secreted to continue the effect initiated by T 4 during induced metamorphosis and to initiate spontaneous metamorphosis; (2) the circulating tadpole hormones can cross-react with antisera prepared against bovine thyrotropin; and (3) the amphibian larval anterior pituitary hormones have immunologic properties common to the mammalian hormones.