Isomalto-oligosaccharides, a prebiotic, functionally augment green tea effects against high fat diet-induced metabolic alterations via preventing gut dysbacteriosis in mice.

High fat diet (HFD)-induced alterations in gut microbiota and resultant 'leaky gut' phenomenon promotes metabolic endotoxemia, ectopic fat deposition, and low-grade systemic inflammation. Here we evaluated the effects of a combination of green tea extract (GTE) with isomalto-oligosaccharide (IMOs) on HFD-induced alterations in mice. Male Swiss albino mice were fed with HFD (58% fat kcal) for 12 weeks. Systemic adiposity, gut derangement parameters and V3-V4 region based 16S rRNA metagenomic sequencing, ectopic fat deposition, liver metabolome analysis, systemic and tissue inflammation, and energy homeostasis markers along with gene expression analysis in multiple tissues were done in mice supplemented with GTE, IMOs or their combination. The combination of GTE and IMOs effectively prevented HFD-induced adiposity and lipid accumulation in liver and muscle while normalizing fasting blood glucose, insulin, glucagon, and leptin levels. Co-administration of GTE with IMOs effectively modulated liver metabolome associated with lipid metabolism. It also prevented leaky gut phenotype and HFD-induced increase in circulating lipopolysaccharides and pro-inflammatory cytokines (e.g. resistin, TNF-α, and IL-1ß) and reduction in anti-inflammatory cytokines (e.g. adiponectin and IL-6). Gene expression analysis across multiple tissues further supported these functional outcomes. Most importantly, this combination improved beneficial gut microbiota (Lactobacillus sp., Bifidobacteria, Akkermansia muciniphila, Roseburia spp.) abundances, restored Firmicutes/Bacteriodetes and improved Prevotella/Bacteroides proportions. In particular, a combination of these two agents has shown improved beneficial effects on multiple parameters studied. Data presented herein suggests that strategically chosen food components might be highly effective in the prevention of HFD-induced alterations and may further be developed as functional foods.

Glucose homeostasis and insulin sensitivity in growth hormone-transgenic mice: a cross-sectional analysis.

In contrast to its stimulatory effects on musculature, bone, and organ development, and its lipolytic effects, growth hormone (GH) opposes insulin effects on glucose metabolism. Chronic GH overexposure is thought to result in insulin insensitivity and decreased blood glucose homeostatic control. Yet, despite the importance of this concept for basic biology, as well as human conditions of GH excess or deficiency, no systematic assessment of the impact of GH over- expression on glucose homeostasis and insulin sensitivity has been conducted. We report that male and female adult GH transgenic mice have enhanced glucose tolerance compared to littermate controls and this effect is not dependent on age or on the particular heterologous GH transgene used. Furthermore, increased glucose-stimulated insulin secretion, augmented insulin sensitivity, and muted gluconeogenesis were also observed in bovine GH overexpressing mice. These results show that markedly increased systemic GH concentration in GH-transgenic mice exerts unexpected beneficial effects on glucose homeostasis, presumably via a compensatory increase in insulin release. The counterintuitive nature of these results challenges previously held presumptions of the physiology of these mice and other states of GH overexpression or suppression. In addition, they pose intriguing queries about the relationships between GH, endocrine control of metabolism, and aging.

Insulin-like growth factor-1 receptor activation prevents high glucose-induced mitochondrial dysfunction, cytochrome-c release and apoptosis.

Vascular disease is the leading cause of morbidity and mortality in patients with diabetes. Persistent hyperglycemia--the dominant metabolic derangement of diabetes, can cause endothelial cell apoptosis. Diabetes is often associated with low insulin like growth factor-1 (IGF-1), and the latter state has been linked to adverse risk profile and increased cardiovascular disease incidence. Since IGF-1 acts as an important survival factor for multiple cell types, this study was to investigate whether IGF-1 exert regulatory effects on high glucose-induced apoptosis of vascular endothelial cells. Exposure to high glucose dose- and time-dependently induced apoptotic changes (e.g., DNA fragmentation, altered mitochondrial membrane potential, and cytochrome-c release) in human umbilical vein endothelial cells (HUVECs). Addition of IGF-1 blocked the high glucose effect in a manner dependent on expression of IGF-1 receptor (IGF-1R) since silencing IGF-1R with small interference RNA could diminish the IGF-1' anti-apoptosis effect. Our findings show that enhanced IGF-1 signaling inhibits glucose-induced apoptosis in HUVECs by reducing mitochondrial dysfunction, and maintaining the mitochondrial retention of cytochrome-c. These results may have therapeutic implications in preventing/reducing diabetes associated endothelial dysfunction.

Influence of TRPV1 on diabetes-induced alterations in thermal pain sensitivity.

A common complication associated with diabetes is painful or painless diabetic peripheral neuropathy (DPN). The mechanisms and determinants responsible for these peripheral neuropathies are poorly understood. Using both streptozotocin (STZ)-induced and transgene-mediated murine models of type 1 diabetes (T1D), we demonstrate that Transient Receptor Potential Vanilloid 1 (TRPV1) expression varies with the neuropathic phenotype. We have found that both STZ- and transgene-mediated T1D are associated with two distinct phases of thermal pain sensitivity that parallel changes in TRPV1 as determined by paw withdrawal latency (PWL). An early phase of hyperalgesia and a late phase of hypoalgesia are evident. TRPV1-mediated whole cell currents are larger and smaller in dorsal root ganglion (DRG) neurons collected from hyperalgesic and hypoalgesic mice. Resiniferatoxin (RTX) binding, a measure of TRPV1 expression is increased and decreased in DRG and paw skin of hyperalgesic and hypoalgesic mice, respectively. Immunohistochemical labeling of spinal cord lamina I and II, dorsal root ganglion (DRG), and paw skin from hyperalgesic and hypoalgesic mice reveal increased and decreased TRPV1 expression, respectively. A role for TRPV1 in thermal DPN is further suggested by the failure of STZ treatment to influence thermal nociception in TRPV1 deficient mice. These findings demonstrate that altered TRPV1 expression and function contribute to diabetes-induced changes in thermal perception.

Involvement of Glucagon in Preventive Effect of Menthol Against High Fat Diet Induced Obesity in Mice.

Glucagon mediated mechanisms have been shown to play clinically significant role in energy expenditure. The present study was designed to understand whether pharmacological mimicking of cold using menthol (TRPM8 modulator) can induce glucagon-mediated energy expenditure to prevent weight gain and related complications. Acute oral and topical administration of TRPM8 agonists (menthol and icilin) increased serum glucagon concentration which was prevented by pre-treatment with AMTB, a TRPM8 blocker. Chronic administration of menthol (50 and 100 mg/kg/day for 12 weeks) to HFD fed animals prevented weight gain, insulin resistance, adipose tissue hypertrophy and triacylglycerol deposition in liver. These effects were not restricted to oral administration, but also observed upon the topical application of menthol (10% w/v). The metabolic alterations caused by menthol in liver and adipose tissue mirrored the known effects of glucagon, such as increased glycogenolysis and gluconeogenesis in the liver, and enhanced thermogenic activity of white and brown adipose tissue. Correlation analysis suggests a strong correlation between glucagon dependent changes and energy expenditure markers. Interestingly, in-vitro treatment of the serum of menthol treated mice increased energy expenditure markers in mature 3T3L1 adipocytes, which was prevented in the presence of non-competitive glucagon receptor antagonist, L-168,049, indicating that menthol-induced increase in serum glucagon is responsible for increase in energy expenditure phenotype. In conclusion, the present work provides evidence that glucagon plays an important role in the preventive effect of menthol against HFD-induced weight gain and related complications.

Infection, immunity, and hormones/endocrine interactions.

Infections and stress, immune responses, and hormones are interconnected, ensuring immune competence to deal with immediate threat of overwhelming infection and metabolic collapse. Emergence of cytokines as key signal mediators and appreciation of autocrine-paracrine influences of hormones have helped explain how signals are transmitted and responses evoked. This has led to possibilities of creating therapies that might be used to enhance protective signals and dampen signals emanating from host and invading organism interaction that might otherwise be detrimental. Correcting certain metabolic abnormalities, such as hyperglycemia and metabolic acidosis, benefits the host by decreasing morbidity and mortality.

Infections in diabetes mellitus and hyperglycemia.

Infections in diabetes mellitus are relatively more common and serious. Diabetic patients run the risk of acute metabolic decompensation during infections, and conversely patients with metabolic decompensation are at higher risk of certain invasive infections. Tight glycemic control is of paramount importance during acute infected or high stress state. Infections in diabetic patients result in extended hospital stays and additional financial burden. Given the risks of not alleviating the metabolic dysregulation and the benefits of decent glycemic control, it is necessary that besides antimicrobial therapy, equal emphasis be placed on intensified glycemic control.

Transient ischemic attack and nephrotic syndrome: Case report and review of literature.

Thrombotic complications in patients with nephrotic syndrome are attributed to a hypercoagulable state. Venous thrombosis is common, but arterial thrombosis occurs less frequently in adult nephrotic patients. We report a case of recurrent transient ischemic attacks as an initial manifestation of nephrotic syndrome due to early-stage membranous glomerulonephritis, review the literature for similar cases, and briefly discuss this potentially life-threatening condition. We observed that transient ischemic attack or ischemic stroke could be the initial manifestation of nephrotic syndrome. Our observation may serve as reminder to consider nephrotic syndrome as a possible contributor when evaluating patients with transient ischemic attacks with no other discernable clues. A high index of suspicion alone avoids the unnecessary withholding of prophylaxis or treatment that can be life saving.

Resistance to the Beneficial Metabolic Effects and Hepatic Antioxidant Defense Actions of Fibroblast Growth Factor 21 Treatment in Growth Hormone-Overexpressing Transgenic Mice.

Fibroblast growth factor 21 (FGF21) modulates a diverse range of biological functions, including glucose and lipid metabolism, adaptive starvation response, and energy homeostasis, but with limited mechanistic insight. FGF21 treatment has been shown to inhibit hepatic growth hormone (GH) intracellular signaling. To evaluate GH axis involvement in FGF21 actions, transgenic mice overexpressing bovine GH were used. Expectedly, in response to FGF21 treatment control littermates showed metabolic improvements whereas GH transgenic mice resisted most of the beneficial effects of FGF21, except an attenuation of the innate hyperinsulinemia. Since FGF21 is believed to exert its effects mostly at the transcriptional level, we analyzed and observed significant upregulation in expression of various genes involved in carbohydrate and lipid metabolism, energy homeostasis, and antioxidant defense in FGF21-treated controls, but not in GH transgenics. The resistance of GH transgenic mice to FGF21-induced changes underlines the necessity of normal GH signaling for the beneficial effects of FGF21.

Heterogeneity in familial dominant Paget disease of bone and muscular dystrophy.

The combination of autosomal dominant, early onset Paget disease of bone (PDB) and muscular dystrophy is an unusual disorder. We recently mapped the disorder in a large family from central Illinois with PDB and proximal limb-girdle type of muscular dystrophy (LGMD), and in 3 additional families with hereditary inclusion body myopathy (HIBM), Paget disease of bone and frontotemporal dementia, to a unique locus on chromosome 9p21.1-q12. The present study describes an unrelated 10-member family with autosomal dominant PDB and a scapuloperoneal type of muscular dystrophy. Clinical, biochemical, and radiological evaluations were performed to delineate clinical features in this family. Progression of the muscular dystrophy begins with weakness in the distal muscles of the legs accompanied by foot drop. EMG and muscle biopsy are compatible with a primary dystrophy. Onset of Paget disease is early, at a mean age of 41 years, with initial distribution in the long bones and eventual infiltration of the spine and pelvis. Creatine phosphokinase (CPK) and alkaline phosphatase levels are elevated in affected individuals. Molecular analyses excluded all known loci for Paget disease of bone, scapuloperoneal muscular dystrophy (SPMD), fascioscapulohumeral muscular dystrophy (FSH), amyotrophic lateral sclerosis (ALS), Bethlem myopathy, two forms of autosomal dominant limb-girdle muscular dystrophy (LGMD), and the critical region for LGMD or HIBM/PDB on chromosome 9p21.1-q12, thus providing evidence for genetic heterogeneity among families with the unique combination of muscular dystrophy and Paget disease of bone.

Hyperparathyroidism and multiple endocrine neoplasia.

Multiple endocrine neoplasia (MEN) syndromes comprise the group of heritable endocrinopathies, MEN 1, MEN 2A, and MEN 2B. Primary hyperparathyroidism caused by multiglandular involvement is usually the initial manifestation in MEN 1, occurring in more than 90% of patients. In patients with MEN 2A, hyperparathyroidism develops less commonly and is usually milder than in MEN 1. Advances in genetics and molecular biology aid in confirming the diagnosis and screening relatives who are carriers or at risk for the disease. Surgery plays an important role in the management of hyperparathyroidism in both MEN 1 and MEN 2A,although the timing and extent of surgery are areas of controversy.Long-term follow-up reveals a high rate of recurrent hyperparathyroidism in MEN 1 despite surgical intervention.

Preservation of blood glucose homeostasis in slow-senescing somatotrophism-deficient mice subjected to intermittent fasting begun at middle or old age.

Poor blood glucose homeostatic regulation is common, consequential, and costly for older and elderly populations, resulting in pleiotrophically adverse clinical outcomes. Somatotrophic signaling deficiency and dietary restriction have each been shown to delay the rate of senescence, resulting in salubrious phenotypes such as increased survivorship. Using two growth hormone (GH) signaling-related, slow-aging mouse mutants we tested, via longitudinal analyses, whether genetic perturbations that increase survivorship also improve blood glucose homeostatic regulation in senescing mammals. Furthermore, we institute a dietary restriction paradigm that also decelerates aging, an intermittent fasting (IF) feeding schedule, as either a short-term or a sustained intervention beginning at either middle or old age, and assess its effects on blood glucose control. We find that either of the two genetic alterations in GH signaling ameliorates fasting hyperglycemia; additionally, both longevity-inducing somatotrophic mutations improve insulin sensitivity into old age. Strikingly, we observe major and broad improvements in blood glucose homeostatic control by IF: IF improves ad libitum-fed hyperglycemia, glucose tolerance, and insulin sensitivity, and reduces hepatic gluconeogenesis, in aging mutant and normal mice. These results on correction of aging-resultant blood glucose dysregulation have potentially important clinical and public health implications for our ever-graying global population, and are consistent with the Longevity Dividend concept.

Interaction of growth hormone receptor/binding protein gene disruption and caloric restriction for insulin sensitivity and attenuated aging.

The correlation of physiological sensitivity to insulin ( vis-à-vis glycemic regulation) and longevity is extensively established, creating a justifiable gerontological interest on whether insulin sensitivity is causative, or even predictive, of some or all phenotypes of slowed senescence (including longevity). The growth hormone receptor/ binding protein gene-disrupted (GHR-KO) mouse is the most extensively investigated insulin-sensitive, attenuated aging model. It was reported that, in a manner divergent from similar mutants, GHR-KO mice fail to respond to caloric restriction (CR) by altering their insulin sensitivity. We hypothesized that maximized insulin responsiveness is what causes GHR-KO mice to exhibit a suppressed survivorship response to dietary (including caloric) restriction; and attempted to refute this hypothesis by assessing the effects of CR on GHR-KO mice for varied slow-aging-associated phenotypes. In contrast to previous reports, we found GHR-KO mice on CR to be less responsive than their ad libitum (A.L.) counterparts to the hypoglycemia-inducing effects of insulin. Further, CR had negligible effects on the metabolism or cognition of GHR-KO mice. Therefore, our data suggest that the effects of CR on the insulin sensitivity of GHR-KO mice do not concur with the effects of CR on the aging of GHR-KO mice.

Specific suppression of insulin sensitivity in growth hormone receptor gene-disrupted (GHR-KO) mice attenuates phenotypic features of slow aging.

In addition to their extended lifespans, slow-aging growth hormone receptor/binding protein gene-disrupted (knockout) (GHR-KO) mice are hypoinsulinemic and highly sensitive to the action of insulin. It has been proposed that this insulin sensitivity is important for their longevity and increased healthspan. We tested whether this insulin sensitivity of the GHR-KO mouse is necessary for its retarded aging by abrogating that sensitivity with a transgenic alteration that improves development and secretory function of pancreatic ß-cells by expressing Igf-1 under the rat insulin promoter 1 (RIP::IGF-1). The RIP::IGF-1 transgene increased circulating insulin content in GHR-KO mice, and thusly fully normalized their insulin sensitivity, without affecting the proliferation of any non-ß-cell cell types. Multiple (nonsurvivorship) longevity-associated physiological and endocrinological characteristics of these mice (namely beneficial blood glucose regulatory control, altered metabolism, and preservation of memory capabilities) were partially or completely normalized, thus supporting the causal role of insulin sensitivity for the decelerated senescence of GHR-KO mice. We conclude that a delayed onset and/or decreased pace of aging can be hormonally regulated.

Changing paradigms in type 2 diabetes mellitus.

Diabetes mellitus has been increasing in prevalence and imposes serious economic burdens on both the developed as well as the developing world. Understanding pathobiological underpinning of chronic progressive disease like diabetes is an imperative that we cannot escape. For several decades now, the focus has remained on a two hit theory which begins with insulin resistance and is followed thereafter by the ß cell failure. Therapies have revolved around this concept with only limited success. Reorientation in our understanding of "islet pathology" should help rethink strategies that would yield better dividends in terms of effective therapy. Role of Glucagon needs to be revisited and incorporated to create treatment regimens addressing the concept of bi-hormonal defect rather than remaining stuck in standalone "insulinopathy." This brief review hopes to initiate/continue that dialogue.

Recombinant human parathyroid hormone therapy (1-34) in an adult patient with a gain-of-function mutation in the calcium-sensing receptor-a case report.

OBJECTIVE: To describe a case of hypocalcemia in a patient with a gain-of-function mutation in the calcium-sensing receptor that was undetected until adulthood and successfully treated with recombinant parathyroid hormone. METHODS: The clinical findings, laboratory data, and a review of the pertinent literature are presented. RESULTS: A 55-year-old woman was hospitalized and seen by the endocrinology consult service for hypocalcemia that was refractory to repeated doses of intravenous calcium gluconate. She expressed concern about chronic leg muscle cramps and paresthesias of the lips and fingertips. In addition, she had no history of neck surgery, neck irradiation, or any autoimmune disease. She was a well-appearing female with no dysmorphic features or skin changes. Laboratory tests revealed hypocalcemia, hyperphosphatemia, hypomagnesemia, and hypovitaminosis D. Her parathyroid hormone concentration (PTH) was low at 14.2 pg/mL. Her PTH and calcium concentrations remained low despite repletion of magnesium and treatment with calcitriol and oral calcium replacement. A 24-hour collection for urinary calcium showed inappropriate hypercalciuria. Medical records showed her hypocalcemia to be chronic. Additionally, several family members had also complained of muscle cramps. A congenital cause of her hypoparathyroidism was considered, and genetic testing confirmed heterozygosity for a gain-of-function mutation in the calcium-sensing receptor gene associated with autosomal dominant familial isolated hypoparathyroidism (ADH). Treatment with subcutaneous recombinant human parathyroid hormone teriparatide (rhPTH [1-34]) 20 mcg twice daily for three days normalized her calcium and phosphorus concentrations. CONCLUSION: rhPTH (1-34) is an effective treatment for patients with hypoparathyroidism due to gain-of-function mutations in the calcium-sensing receptor. ADH can be insidious in presentation and the diagnosis can be missed unless there is a high index of suspicion.

Endocrine and metabolic changes during sepsis: an update.

The authors have reviewed the most recent and relevant literature from which reasonable conclusions may be drawn. This article highlights important endocrine and metabolic changes, and provides possible explanations for observed perturbations. Obviously infectious disease specialists are not charged with the primary responsibility of addressing these issues, which have largely remained the domain of endocrinologists and intensivists. However, infectious disease specialists use a variety of drugs that can contribute to these abnormalities. Therefore, a constant dialogue between specialists would enhance the quality of care and also contribute immensely to favorable outcomes.

Glucose control and cardiovascular outcomes: reorienting approach.

Cardiovascular disease accounts for nearly 70% of morbidity and mortality in patients with diabetes mellitus. Strides made in diabetes care have indeed helped prevent or reduce the burden of microvascular complications in both type 1 and type 2 diabetes. However, the same cannot be said about macrovascular disease in diabetes. Several prospective trials so far have failed to provide conclusive evidence of the superiority of glycemic control in reducing macrovascular complications or death rates in people with advanced disease or those with long duration of diabetes. There are trends that suggest that benefits are restricted to those with lesser burden and shorter duration of disease. Furthermore, it is also suggested that benefits might accrue but it would take a longer time to manifest. Clinicians are faced with the challenge to decide how to triage patients for intensified care vs less intense care. This review focuses on evidence and attempts to provide a balanced view of the literature that has radically affected how physicians treat patients with macrovascular disease. It also takes cognizance of the fact that the natural course of the disease may be changing as well, possibly related to better overall awareness and possibly improved access to information about better individual healthcare. The review further takes note of some hard held notions about the pathobiology of the disease that must be interpreted with caution in light of new and emerging data. In light of recent developments ADA and EASD have taken step to provide some guidance to clinicians through a joint position statement. A lot more research would be required to figure out how best to manage macrovascular disease in diabetes mellitus. Glucocentric stance would need to be reconsidered, and attention paid to concurrent multifactorial interventions that seem to be effective in reducing vascular outcomes.

Immunotherapy in miscellaneous medical disorders Graves ophthalmopathy, asthma, and regional painful syndrome.

In Graves ophthalmopathy, immunotherapy is offering an opportunity of reducing bad outcomes that lead to disfigurement and impairment of vision. These therapies are not perfect; however, we now have a chance to achieve better outcomes. In asthma, immune therapy using passive immunity targeting key proinflammatory cytokine/chemokines and medications of their effects has opened an avenue of research into a safe and durable therapy. Omalizumab appears to be safe and effective in clinical use. In regional pain syndrome, immune mechanisms may be involved in sustaining long-standing pain, and IVIG may moderate pain sensitivity by reducing immune activation.

A pituitary abscess masquerading as recurrent hypernatremia and aseptic meningitis.

Pituitary abscess is a rare condition. In the setting of multiple surgical interventions, the risk of its development increases. A 49-year-old man presented with episodes of altered mental status. He had two surgeries for a recurrent suprasellar arachnoid cyst. The second surgery was complicated by a persistent cerebrospinal fluid (CSF) leak that required two repairs following which he developed panhypopituitarism and central diabetes insipidus. Twelve months after his last surgery he was diagnosed with aseptic meningitis. This was followed by recurrent hospitalisations for severe hypernatremia blamed on poor medication compliance. He was subsequently hospitalised for the evaluation of a febrile illness. Brain MRI showed ventriculitis and enhancement of the sella. Exploratory surgery revealed a purulent collection in the sella and a mucosal graft which had been used to repair the CSF leak. After drainage of pus and replacement of the graft he recovered completely but requiring life-long hormonal replacement.