Pilot Study to Evaluate the Effect of Short-Term Improvement in Vitamin D Status on Glucose Tolerance in Patients With Type 2 Diabetes Mellitus

ObjectiveTo study the effect of improvement in vitamin D status on glucose tolerance in Asian Indian patients with moderately controlled type 2 diabetes mellitus (T2DM).MethodsThis randomized, double-blind, placebocontrolled pilot study was conducted in 28 Asian Indian patients with T2DM. Study participants were randomly assigned to a vitamin D-treated group (group D) or a placebo group (group P). Serum 25-hydroxyvitamin D, hemoglobin A1c, and serum fructosamine levels were measured, and an oral glucose tolerance test (OGTT) was performed in all patients at baseline and 4 weeks after intervention. During the OGTT, plasma glucose and serum insulin levels were measured at 0, 30, 60, 90, and 120 minutes. The unpaired t test was used to compare the groups at baseline and to compare the differences in changes from baseline to 4 weeks between the 2 study groups.ResultsGroup D and group P were similar with respect to their fasting plasma glucose and serum insulin concentrations, post-OGTT plasma glucose and serum insulin levels, and hemoglobin A1c and fructosamine values at baseline. Serum 25-hydroxyvitamin D levels increased significantly in group D at 4 weeks. No significant differences were found between the groups at baseline and 4 weeks with respect to serum fructosamine, fasting plasma glucose and serum insulin, post-OGTT plasma glucose and serum insulin levels, and homeostasis model assessment of insulin resistance.ConclusionIn this study, short-term improvement in vitamin D status was not associated with improvement in glucose tolerance, insulin secretion, or insulin sensitivity in Asian Indian patients with moderately controlled T2DM.(Endocr Pract. 2010;16:600-608)     

Role of Insulin Signaling in Maintaining Energy Homeostasis

ObjectiveTo examine the role that insulin signaling plays in modulating metabolic functions involving both peripheral and hypothalamic systems.MethodsWe review the literature regarding insulin signaling as it relates to energy homeostasis.ResultsInsulin signaling in the periphery is known to affect hepatic glucose production and glucose uptake in muscle and adipose tissue. In the brain, insulin is involved in a variety of signaling pathways that control positive and negative aspects of food intake and energy metabolism. Disruption of insulin signaling can affect key cellular pathways that serve to maintain energy balance and glucose homeostasis, which can then lead to insulin resistance and progression toward various metabolic disorders, including cardiovascular disease, obesity, and type 2 diabetes. The use of exogenous insulin as therapy for patients with type 2 diabetes is traditionally associated with increases in weight.ConclusionAn enhanced understanding of how these insulin signaling pathways function may provide answers about how to control weight gain associated with exogenous insulin use. Pharmacologic agents, such as the long-acting insulin analogues and particularly insulin detemir, that may reduce these weight effects hold considerable advantage. (Endocr Pract. 2008;14:373-380)     

Syndromic Insulin Resistance: Models for the Therapeutic Basis of the Metabolic Syndrome and Other Targets of Insulin Resistance

ObjectiveTo investigate the link between insulin resistance and the metabolic syndrome how to develop treatment approaches.MethodsWe present 3 cases of extreme syndromic insulin resistance: lipodystrophy, autoantibodies to the insulin receptor, and mutations in the insulin receptor gene, with accompanying discussion of pathophysiology and treatment.ResultsIn lipodystrophy, insulin resistance is a direct consequence of leptin deficiency, and thus leptin replacement reverses metabolic syndrome abnormalities, including diabetes and hypertriglyceridemia. The insulin “receptoropathies,” including autoantibodies to the insulin receptor and insulin receptor gene mutations, are characterized by extreme insulin resistance and ovarian hyperandrogenism, without dyslipidemia or fatty liver disease. Autoantibodies to the insulin receptor can be treated using an immunosuppressive paradigm adapted from treatment of other autoimmune and neoplastic conditions. Leptin treatment has shown some success in treating hyperglycemia in patients with insulin receptor gene mutations. Treatment for this condition remains inadequate, and novel therapies that bypass insulin receptor signaling, such as enhancers of brown adipose tissue, are needed.ConclusionsWe present a clinical approach to the treatment of syndromic insulin resistance. The study of rare diseases that replicate the metabolic syndrome, with clear-cut pathophysiology, promotes understanding of novel physiology and development of targeted therapies that may be applicable to the broader population with obesity, insulin resistance, and diabetes. (Endocr Pract. 2012; 18:763-771)     

Insulin Resistance and Thrombogenesis: Recent Insights and Therapeutic Implications

ObjectiveTo review the relationship between insulin resistance and thrombogenesis, especially in the context of obesity, diabetes, and cardiovascular disease, and to discuss therapeutic implications.MethodsThe pertinent peer-reviewed literature was examined for evidence in support of the aforementioned relationship, and the reported efficacy of various therapeutic interventions was assessed.ResultsRobust evidence indicates that insulin resistance and enhanced thrombogenesis are closely related pathophysiologic mechanisms, especially in the presence of obesity. Thus, targeting insulin resistance and thrombogenesis may be of value in the prevention and management of type 2 diabetes and associated cardiovascular morbidity and mortality. Many proven preventive and therapeutic strategies, such as weight loss, exercise, and various pharmaceutical agents, affect both thrombogenesis and insulin resistance.ConclusionBoth insulin resistance and thrombogenesis contribute to the morbidity and mortality associated with obesity, diabetes, and cardiovascular disease. Effective measures for prevention and management of diabetes and cardiovascular disease also tend to improve insulin sensitivity and to ameliorate abnormalities in coagulation, fibrinolysis, and platelet function. (Endocr Pract. 2007;13:679-686)     

Early evidence of ethnic differences in cardiovascular risk: cross sectional comparison of British South Asian and white children

ObjectivesTo examine whether British South Asian children differ in insulin resistance, adiposity, and cardiovascular risk profile from white children.DesignCross sectional study.SettingPrimary schools in 10 British towns.ParticipantsBritish children aged 8 to 11 years (227 South Asian and 3415 white); 73 South Asian and 1287 white children aged 10 and 11 years provided blood samples (half fasting, half after glucose load).ResultsMean ponderal index was lower in South Asian children than in white children (mean difference −0.43 kg/m³, 95% confidence interval −0.13 kg/m³ to −0.73 kg/m³). Mean waist circumferences and waist:hip ratios were similar. Mean insulin concentrations were higher in South Asian children (percentage difference was 53%, 14% to 106%, after fasting and 54%, 19% to 99%, after glucose load), though glucose concentrations were similar. Mean heart rate and triglyceride and fibrinogen concentrations were higher among South Asian children; serum total, low density lipoprotein, and high density lipoprotein cholesterol concentrations were similar in the two groups. Differences in insulin concentrations remained after adjustment for adiposity and other potential confounders. However, the relations between adiposity and insulin concentrations (particularly fasting insulin) were much stronger among South Asian children than among white children.ConclusionsThe tendency to insulin resistance observed in British South Asian adults is apparent in children, in whom it may reflect an increased sensitivity to adiposity. Action to prevent non-insulin dependent diabetes in South Asian adults may need to begin during childhood.

What is already known on this topic

Compared with white people British South Asians are at increased risk of coronary heart disease, stroke, and non-insulin dependent diabetesThere is evidence that these conditions originate in early life

What this study adds

British South Asian children show higher average levels of insulin and insulin resistance than white childrenThese ethnic differences in insulin resistance in childhood are not associated with corresponding differences in adiposity, particularly central adiposityInsulin metabolism seems to be more sensitive to a given degree of adiposity among the South Asian children compared with white childrenThe prevention of insulin resistance and its consequences may need to begin during childhood, particularly in South Asians     

Endpiece: Hospital league tables 1830

ObjectiveTo assess the long term effects of advice to restrict dietary sodium in adults with and without hypertension.DesignSystematic review and meta-analysis of randomised controlled trials.OutcomesMortality, cardiovascular events, blood pressure, urinary sodium excretion, quality of life, and use of antihypertensive drugs.ResultsThree trials in normotensive people (n=2326), five trials in those with untreated hypertension (n=387), and three trials in people being treated for hypertension (n=801) were included, with follow up from six months to seven years. The large high quality (and therefore most informative) studies used intensive behavioural interventions. Deaths and cardiovascular events were inconsistently defined and reported. There were 17 deaths, equally distributed between intervention and control groups. Systolic and diastolic blood pressures were reduced (systolic by 1.1 mm Hg, 95% confidence interval 1.8 to 0.4 mm Hg; diastolic by 0.6 mm Hg, 1.5 to −0.3 mm Hg) at 13 to 60 months, as was urinary 24 hour sodium excretion (by 35.5 mmol/24 hours, 47.2 to 23.9). Degree of reduction in sodium intake and change in blood pressure were not related.ConclusionsIntensive interventions, unsuited to primary care or population prevention programmes, provide only small reductions in blood pressure and sodium excretion, and effects on deaths and cardiovascular events are unclear. Advice to reduce sodium intake may help people on antihypertensive drugs to stop their medication while maintaining good blood pressure control.

What is already known on this topic

Restricting sodium intake in people with hypertension reduces blood pressureLong term effects (on blood pressure, mortality, and morbidity) of reduced salt intake in people with and without hypertension are unclear

What this study adds

Few deaths and cardiovascular events have been reported in salt reduction trialsMeta-analysis shows that blood pressure was reduced (systolic by 1.1 mm Hg, diastolic by 0.6 mm Hg) at 13 to 60 months, with a reduction in sodium excretion of almost a quarter (35.5 mmol/24 hours)The interventions used were highly intensive and unsuited to primary care or population prevention programmesLower salt intake may help people on antihypertensive drugs to stop their medication while maintaining good control of blood pressure, but there are doubts about effects of sodium reduction on overall health     

Sex Hormone-Binding Globulin and The Risk for Metabolic Syndrome in Children of South Asian Indian Origin

ObjectiveTo determine whether the plasma level of sex hormone-binding globulin (SHBG) identifies South Asian Indian children at risk for metabolic syndrome.MethodsAdults and their children aged 5 to 9 years were recruited at the annual health fair at the Hindu temple serving the South Asian Indian community in Louisville, Kentucky. Anthropometric data were collected in adults and children, and blood pressure, lipid, and glucose levels were measured in adults. SHBG levels were measured in children using a fingerstick blood sample. In adults, metabolic syndrome was diagnosed according to the International Diabetes Federation criteria. Twelve months later, follow-up anthropometric data were obtained for a portion of the children.ResultsThe study included 30 sets of parents and 30 children. The prevalence of metabolic syndrome among 310 adults attending the health fair was 42% in men and 39% in women. Children with 1 parent with metabolic syndrome had 24% lower SHBG levels that increased to 55% of both parents had metabolic syndrome. SHBG levels were inversely related to waist circumference and to body mass index percentile. Both SHBG and waist circumference predicted weight gain over 1 year in children.ConclusionsLow SHBG levels were found in South Asian Indian children whose parents had attributes of metabolic syndrome. The dose dependency of SHBG is consistent with inheritance of a genetic trait, and if the results are applicable to other racial/ethnic groups, SHBG may be a useful marker to identify at-risk children for early intervention. (Endocr Pract. 2012;18:668-675)     

Lipid Accumulation Product,Visceral Adiposity Index,And Chinese Visceral Adiposity Index As Markers Of Cardiometabolic Risk In Adult Growth Hormone Deficiency Patients: A Cross-Sectional Study

Objective: Adult growth hormone deficiency (AGHD) is associated with cardiometabolic risk factors. Given that cardiovascular disease (CVD) is an important cause of morbidity and mortality in the AGHD population, there is a need for alternative, noninvasive methods of assessing cardiometabolic risk in this population. The Chinese visceral adiposity index (CVAI) is a new marker of visceral fat dysfunction based on age, body mass index (BMI), waist circumference (WC), and metabolic parameters. CVAI is well correlated with insulin resistance (IR) and is better at predicting metabolic syndrome (MS) than BMI and WC. This study aims to examine the reliability of the lipid accumulation product (LAP), visceral adiposity index (VAI), and CVAI as cardiometabolic risk markers in AGHD patients.Methods: A total of 91 patients diagnosed with AGHD were divided into 4 groups according to CVAI quartile. We investigated the relationship between the patients' clinical and biochemical features, cardiometabolic risk assessed by cardiometabolic risk indices, the Framingham and atherosclerotic cardiovascular disease (ASCVD) risk scores, LAP, VAI, and CVAI.Results: The CVAI scores of patients were significantly higher than those of control patients. Increased CVAI significantly correlated with higher BMI, WC, waist-hip ratio (WHR), and triglycerides (TG), Framingham risk score and atherosclerotic cardiovascular disease lifetime risk score (P≤.001), with lower growth hormone (GH) and high-density lipoprotein cholesterol (HDL-C) levels (P≤.001).Conclusion: Our results suggest that CVAI may be a good marker of cardiometabolic risk in AGHD patients and could be used to diagnose CVD development and vascular accidents.Abbreviations: AGHD = adult growth hormone deficiency; ASCVD = atherosclerotic cardiovascular disease; AUROC = area under the receiver operating characteristic curve; BMI = body mass index; CVAI = Chinese visceral adiposity index; CVD = cardiovascular disease; DBP = diastolic blood pressure; GH = growth hormone; GHRT = GH replacement therapy; HDL-C = high-density lipoprotein cholesterol; IGF-1 = insulin like factor-1; IGFBP-3 = insulin like factor binding protein-3; IR = insulin resistance; LAP = lipid accumulation product; MS = metabolic syndrome; SBP = systolic blood pressure; TC = total cholesterol; TG = triglycerides; VAI = visceral adiposity index; WC = waist circumference; WHR = waist-to-hip ratio     

Role of the Endocannabinoid System in Management of Patients with Type 2 Diabetes Mellitus and Cardiovascular Risk Factors

ObjectiveTo review the role of the endogenous cannabinoid system (ECS) in the peripheral and central regulation of food intake, appetite, and energy storage and discuss the potential for the ECS to be an important target for lowering cardiovascular risk.MethodsMaterials used for this article were identified through a MEDLINE search of the pertinent literature (1975 to present), including English-language randomized controlled, prospective, cohort, review, and observational studies. We summarize the available experimental and clinical data.ResultsThe ECS is composed of two 7-transmembrane G protein-coupled cannabinoid receptor subtypes, CB₁ and CB₂, endogenous cannabinoid ligands (anandamide and 2-arachidonoylglycerol), and the enzymes that synthesize and break down the ligands. Understanding the role of the ECS in central and peripheral metabolic processes related to the regulation of food intake and energy balance as well as the endocrine role of excess adipose tissue, particularly visceral adipose tissue, and its promotion of global cardiometabolic risk has led to the development of pharmacologic agents with potential for blockade of CB₁ receptors. In several studies, rimonabant (20 mg daily) demonstrated a favorable effect on various risk factors for cardiovascular disease, including dyslipidemia, abdominal obesity, insulin resistance, blood pressure, and measures of inflammation.ConclusionThe ECS has been shown to have a key role in the regulation of energy balance, and modulation of this system may affect multiple cardiometabolic risk factors. Clinical studies involving pharmacologic blockade of CB₁ receptors in overweight patients with and without type 2 diabetes have demonstrated effective weight loss and improvements in several risk factors for cardiovascular disease. (Endocr Pract. 2007;13:790-804)     

Treatment of Hypogonadism with Testosterone in Patients with Type 2 Diabetes Mellitus

ObjectiveTo investigate the effect of testosterone treatment on insulin resistance, glycemic control, and dyslipidemia in Asian Indian men with type 2 diabetes mellitus (T2DM) and hypogonadism.MethodsWe conducted a double-blind, placebo-controlled, crossover study in 22 men, 25 to 50 years old, with T2DM and hypogonadism. Patients were treated with intramuscularly administered testosterone (200 mg every 15 days) or placebo for 3 months in random order, followed by a washout period of 1 month before the alternative treatment phase. The primary outcomes were changes in fasting insulin sensitivity (as measured by homeostasis model assessment [HOMA] in those patients not receiving insulin), fasting blood glucose, and hemoglobin A1c. The secondary outcomes were changes in fasting lipids, blood pressure, body mass index, waist circumference, waist-to-hip ratio, and androgen deficiency symptoms. Statistical analysis was performed on the delta values, with the treatment effect of placebo compared with the effect of testosterone.ResultsTreatment with testosterone did not significantly influence insulin resistance measured by the HOMA index (mean treatment effect, 1.67 ± 4.29; confidence interval, -6.91 to 10.25; P > .05). Mean change in hemoglobin A1c (%) (-1.75 ± 5.35; -12.46 to 8.95) and fasting blood glucose (mg/dL) (20.20 ± 67.87; -115.54 to 155.94) also did not reach statistical significance. Testosterone treatment did not affect fasting lipids, blood pressure, and anthropometric determinations significantly.ConclusionIn this study, testosterone treatment showed a neutral effect on insulin resistance and glycemic control and failed to improve dyslipidemia, control blood pressure, or reduce visceral fat significantly in Asian Indian men with T2DM and hypogonadism. (Endocr Pract. 2010;16:570-576)     

Vitamin D,Calcium, and Cardiovascular Mortality: A Perspective from A Plenary Lecture Given at the Annual Meeting of the American Association of Clinical Endocrinologists

ObjectiveTo examine data showing associations between serum 25-hydroxyvitamin D levels and calcium intake and cardiovascular mortality.MethodsThe articles reviewed include those published from 1992-2011 derived from search engines (PubMed, Scopus, Medscape) using the following search terms: vitamin D, calcium, cardiovascular events, cardiovascular mortality, all-cause mortality, vascular calcification, chronic kidney disease, renal stones, and hypercalci- uria. Because these articles were not weighted (graded) on the level of evidence, this review reflects my own perspective on the data and how they should be applied to clinical management.ResultsFor skeletal health, vitamin D and calcium are both needed to ensure proper skeletal growth (modeling) and repair (remodeling). Nutritional deficiencies of either vitamin D or calcium may lead to a spectrum of metabolic bone disorders. Excessive consumption of either nutrient has been linked to a variety of medical disorders, such as hypercalcemia or renal stones. There have also been associations between vitamin D or calcium intake and cardiovascular disease. However, neither of these associations have established evidence nor known causality for increasing cardiovascular risk or all-cause mortality in patients with creatinine clearances greater than 60 mL/ min. In patients with more severe chronic kidney disease, stronger data link excess calcium (or phosphorus) intake and increase in vascular calcification, but not mortality. The safe upper limit for vitamin D intake is at least 4000 IU daily and probably 10 000 IU daily; for calcium, the safe upper limit is between 2000 and 3000 mg daily.ConclusionsWhile no solid scientific evidence validates that serum vitamin D levels between 15 and 70 ng/ mL are associated with increased cardiovascular disease risk, stronger but inconsistent evidence shows an association between calcium supplementation greater than 500 mg daily and an increase in cardiovascular disease risk. Most professional societies suggest that replacement levels of these nutrients be personalized with the goal of reaching a 25-hydroxyvitamin D concentration between 30 and 50 ng/ mL and a calcium intake of 1200 mg daily. (Endocr Pract. 2011;17:798-806)     

Influence of Salt Intake on Association of Blood Uric Acid with Hypertension and Related Cardiovascular Risk

BackgroundA relationship of blood uric acid (UA) with hypertension and cardiovascular risk is under debate thus salt intake is hypothesized to contribute to such associations.MethodsIn this cross-sectional study, stratified cluster random sampling elicited a sample of 1805 Kazakhs with 92.4% compliance. Hypertension and moderate-or-high total cardiovascular risk (mTCR) were defined according to guidelines. Sodium intake was assessed by urinary sodium excretion. Prevalence ratios (PRs) were used to express associations of UA with hypertension and mTCR.ResultsIn the highest tertile of sodium intake in women, the adjusted PRs (95% confidence intervals) of low to high quartiles compared with the lowest quartile of UA, were 1.22(0.78–1.91), 1.18(0.75–1.85), and 1.65(1.09–2.51) for hypertension and 1.19(0.74–1.90), 1.39(0.91–2.11), and 1.65(1.10–2.47) for mTCR (P for trend <0.05). However, these findings were not shown for other sodium intake levels. There were similar results in men. PRs markedly increased with a concomitant increase in UA and sodium intake and there was a significant interaction (P = 0.010) for mTCR with PRs of 1.69(1.10–2.60) for men and 3.70(2.09–6.52) for women in those with the highest compared with the lowest quartile of UA and tertile of sodium intake. Similar findings were shown for hypertension.ConclusionsThis study implied that a high salt intake may enhance the associations of UA with hypertension and cardiovascular risk.     

Association of Plasma Parathyroid Hormone with Metabolic Syndrome and Risk for Cardiovascular Disease

ObjectiveTo review the current literature investigating the association of plasma parathyroid hormone (PTH) with the prevalence of metabolic syndrome and the risk for cardiovascular disease (CVD).MethodsWe conducted a search of PubMed and Medline database using the terms hyperparathyroidism, metabolic syndrome, hypertension, hyperlipidemia, hyper-glycemia, and CVD. We reviewed relevant studies from 2004 to 2012.ResultsThe current literature assessing the association of plasma PTH levels with metabolic syndrome and CVD is inconsistent; however, positive associations among hyperparathyroidism, metabolic syndrome, and CVD were found in a majority of the studies. The differences in the study populations may partly explain the mixed results.ConclusionIn the general population, a high serum PTH level predisposes patients to CVD mortality. Further research is needed to determine the role of PTH in the etiology of metabolic syndrome and CVD. (Endocr Pract. 2013;19:712-717)     

The impact of central obesity as a prerequisite for the diagnosis of metabolic syndrome

Objective: To compare the prevalence of metabolic syndrome (MS) defined according to the American Heart Association (AHA)/National Heart Lung and Blood Institute (NHLBI) and the International Diabetes Federation (IDF) and to determine the effect of the presence of central obesity on the phenotype (insulin resistance and other cardiovascular risk factors) associated with MS. Research Methods and Procedures: We studied 4723 Chinese, Malays, and Asian Indians living in Singapore. Each individual was categorized according to the five criteria for MS as defined by the AHA/NHLBI and the IDF. The population was categorized according to the presence of three or more criteria and then further subcategorized according to the presence or absence of central obesity. Characteristics of each group were compared using ANOVA and the χ² test. Results: MS was present in 20.2% (IDF) and 26.9% (AHA/NHLBI) of the population. Of the population, 6.7% exhibited three or more features of MS without central obesity. Use of the IDF definition, which requires central obesity, is associated with greater insulin resistance but similar levels of other cardiovascular disease risk factors than the use of the AHA/NHLBI definition, which does not require central obesity. Discussion: In this Southeast Asian population, the IDF and the AHA/NHLBI definitions of MS identify different segments of the MS population. The IDF definition may be more appropriate for the identification of those with insulin resistance and increased risk of type 2 diabetes. In contrast, the AHA/NHLBI definition may better identify those at increased risk of cardiovascular disease.     

Pancreatic β-CELL Dysfunction in Polycystic Ovary Syndrome: the Role of Metformin

ObjectiveTo determine whether the administration of 6 months of daily metformin treatment in women with polycystic ovary syndrome (PCOS) would significantly improve pancreatic β-cell function as measured by an increase in the disposition index.MethodsWe enrolled women with PCOS from a private practice and from the Mount Sinai Hospital Endocrinology Clinic. All patients underwent frequently sampled intravenous glucose tolerance tests both on and off 500 to 1000 mg of twice daily metformin. Values of insulin sensitivity, glucose effectiveness, acute insulin response to glucose, and disposition index were calculated for each test. The product of acute insulin response to glucose and insulin sensitivity yielded the disposition index and estimated the degree of β-cell compensation for insulin resistance.ResultsWe enrolled 14 women. We observed no significant changes in insulin sensitivity, glucose effectiveness, or acute insulin response to glucose, disposition index, or distributed glucose at time 0 before or after metformin treatment. Patients with PCOS treated with metformin remained statistically on the same hyperbolic curve, which is consistent with previously reported results of the effect of metformin on β-cell function. In contrast, the proportional change in disposition index correlated significantly with the proportional change in insulin sensitivity. Patients whose insulin sensitivity decreased after treatment showed a proportional decrease in disposition index, while patients whose insulin sensitivity increased showed a proportional increase in disposition index.ConclusionsOur findings suggest that acute insulin response to glucose does not proportionately change to match change in insulin sensitivity. Thus, there may be a β-cell defect in women with PCOS. (Endocr Pract. 2012;18:685-693)     

Cystic Fibrosis-Related Diabetes Mellitus: Etiology,Evaluation, and Management

ObjectiveTo review the pathophysiology, diagnosis, and management of cystic fibrosis-related diabetes mellitus (CFRD).MethodsWe performed a MEDLINE search of the literature, using the search terms “cystic fibrosis-related diabetes, “CFRD,” and “cystic fibrosis and diabetes,” to identify pertinent articles available in English.ResultsIn patients with cystic fibrosis (CF), CFRD is a major cause for an accelerated decline in health. It is the result of multiple pathophysiologic mechanisms, including destruction of pancreatic islet cells, impaired hepatic response to the antigluconeogenic effects of insulin, and impaired insulin sensitivity. Nutritional management and adequate caloric intake are paramount to successful management of CF. Although insulin remains the standard of care for treating CFRD in conjunction with fasting hyperglycemia, a small but growing body of literature supports the use of oral therapies. In this article, we discuss the benefits of and possible adverse reactions to the various classes of oral and injectable agents used in the treatment of diabetes mellitus, with special attention to the population of patients with CF.ConclusionOrally administered agents can have a role in the treatment of CFRD. Further study is needed to determine the optimal combination of therapeutic modalities for CFRD. (Endocr Pract. 2008;14:1169-1179)     

Glycemia and Cardiova Scular Disease in Type 1 Diabetes Mellitus

ObjectiveTo evaluate the role of glycemic control in the development of cardiovascular disease (CVD) in type 1 diabetes mellitus (DM).MethodsWe review the literature regarding coronary atherosclerosis, coronary artery calcification, and the epidemiologic studies related to the role of glycemia and the classic risk factors for coronary artery disease (CAD) in type 1 DM.ResultsFour prospective studies (Wisconsin Epidemiologic Study of Diabetic Retinopathy, EURODIAB, Steno Diabetes Center Study of Adults With Type 1 DM, and Pittsburgh Epidemiology of Diabetes Complications study) do not show that glycemic control predicts CAD occurrence. Findings from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study show that compared with conventional insulin therapy, intensive insulin therapy reduces CVD among patients with type 1 DM and is associated with lower prevalence of coronary artery calcification. The discrepancies between the findings from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study and the Pittsburgh Epidemiology of Diabetes Complication study are likely due to differences between the study populations and the lower prevalence of renal disease in the former study. Besides duration of DM and albuminuria/overt nephropathy, insulin resistance is a major determinant of CAD associated with type 1 DM.ConclusionsDiscrepant study results regarding the relationship between glycemia and CAD/coronary artery calcification may be related to the prevalence of renal disease and the presence of the metabolic syndrome. Published data suggest that addressing traditional risk factors including albuminuria, the metabolic syndrome, and inflammatory markers is better for preventing and treating CAD than focusing exclusively on glycemic control, which is still necessary for preventing microvascular complications. Furthermore, there is a synergistic effect of glycemic control and albuminuria on the development of CVD. (Endocr Pract. 2008;14:912-923)     

Proinflammatory and Antiinflammatory Attributes of Fetu Iν-A: A Novel Hepatokine Modulating Cardiovascular and Glycemic Outcomes in Metabolic Syndrome

ObjectiveFetuin-A is a novel hepatokine. The number of biologic roles attributed to fetuin-A has increased exponentially in the past decade. The objective of this review is to discuss the pathophysiology of fetuin-A action, its proinflammatory and antiinflammatory attributes in different biological systems throughout the body, and pharmacologic interventions that modulate fetuin-A levels.MethodsPubMed, Medline, and Embase search for articles published to July 2014, using the terms “alpha-2-hs-glycoprotein” [MeSH Terms] OR “alpha-2-hs-glyco-protein” [All Fields] OR “fetuin a” [All Fields].ResultsFetuin-A is the endogenous ligand for Toll-like receptor-4 activation, for lipid-induced insulin resistance. Fetuin-A has inverse interaction with adiponectin. Increased fetuin-A is a risk factor for diabetes and fatty liver disease in normoglycemia and prediabetes. Fetuin-A is a negative acute-phase reactant in sepsis and endotoxemia, promotes wound healing, and is neuroprotec-tive in Alzheimer’s disease. Decreased fetuin-A predicts increased disease activity in obstructive lung disease, Crohn’s disease, and ulcerative colitis. Both elevated and reduced fetuin-A may be linked with increased cardiovascular events.ConclusionFetuin-A is a pleotropic molecule with diverse (sometimes even contradictory) effects in different systems, brought about by interaction with a variety of receptors, including the insulin, transforming growth factor-β, and a plethora of Toll-like receptors. As a proinflammatory molecule, fetuin-A contributes to insulin resistance and is an important link between liver, adipose tissue, and muscles. Fetuin-A is neuroprotective and plays an important antiinflammatory role in sepsis and autoimmune disorders. Pharmacologic options are limited in modulating serum fetuin-A, but salsalates, curcumin, and vitamin D are promising agents of the future. (Endocr Pract. 2014;20:1345-1351)     

Preclinical Atherosclerosis in Patients with Prolactinoma

ObjectiveThe aim of this study was to evaluate the effect of hyperprolactinemia on body fat, insulin sensitivity, inflammatory markers, and cardiovascular risk in patients with prolactinoma.MethodsThe study included 35 untreated hyperprolactinemic patients with pituitary adenomas, and 36 age-, gender-, and body mass index (BMI)-matched healthy controls without any known disease. Serum glucose, insulin, homeostasis model assessment of insulin resistance (HOMA-IR, lipid profile, high-sensitivity C-reactive protein (hs-CRP), and heart-type fatty acid binding protein (H-FABP) levels were measured. Waist and hip circumference (WC and HC) were measured in all the participants. The body fat percentage was measured, and the visceral fat and abdominal fat percentages were measured via bioelectrical impedance (BIA). In addition, carotid intima media thickness (CIMT) was measured using high-resolution B-mode ultrasound.ResultsThe serum glucose level, HOMA-IR, triglyceride level, and SC were significantly higher in the patient group than in the control group. The hs-CRP level and CIMT were significantly higher in the hyperprolactinemic patients. Visceral and truncal fat percentages were significantly higher in the patients with prolactinoma. H-FABP levels were similar in the 2 groups, and there was a positive correlation between the prolactin (PRL) and H-FABP protein levels.ConclusionsBased on the present findings, hyperprolactinemia is associated with preclinical atherosclerosis and metabolic abnormalities. Patients with hyperprolactinemia might experience cardiovascular disease in the long term. Metabolic control should be achieved in addition to the control of hyperprolactinemia in the clinical management of patients diagnosed with prolactinoma. (Endocr Pract. 2014;20:447-451)     

Role of Insulin Sensitizers on Cardiovascular Risk Factors in Polycystic Ovarian Syndrome: A Meta-Analysis

Objective: Polycystic ovarian syndrome (PCOS) is associated with an increase in cardiovascular (CV) risk factors such as insulin resistance, with accompanying hyperinsulinemia and hyperlipidemia, which are predisposing factors for type 2 diabetes mellitus and CV disease. The aim of this meta-analysis is to examine the effect of insulin sensitizers on clinical and biochemical features of PCOS and risk factors for CV disease.Methods: A systematic literature review was conducted, and randomized controlled clinical trials were identified by a search of bibliographic databases: Medline database (from 1966 forward), EMBASE (January 1985 forward), and Cochrane Central Register of Controlled Trials. Reviews of reference lists further identified candidate trials. Data was independently abstracted in duplicate by 2 investigators using a standardized data-collection form. Articles without a comparison group and randomization allocation were excluded. Reviewers worked independently and in duplicate to determine the methodological quality of trials, then collected data on patient characteristics, interventions, and outcomes.Results: Of 455 studies, 44 trials were eligible. A random effects model was used. Significant unadjusted results favoring treatment with insulin sensitizers were obtained for body mass index (BMI) (effect size [ES] of 0.58), waist to hip ratio (WHR) (ES of 0.02), low-density-lipoprotein cholesterol (LDL-C) (ES of 0.11), fasting insulin (ES of 2.82), fasting glucose (ES of 0.10), free testosterone (ES of 1.88), and androstenedione level (ES of 0.76).Conclusion: Treatment with insulin sensitizers in women with PCOS results in improvement in CV factors such as BMI, WHR, LDL-C, fasting insulin, glucose, free testosterone, and androstenedione.Abbreviations: BMI = body mass index CI = confidence interval CVD = cardiovascular disease DM = diabetes mellitus EE = ethinyl estradiol ES = effect size FSH = follicle-stimulating hormone GnRH = gonadotropin-releasing hormone HDL = high-density lipoprotein HDL-C = high-density-lipoprotein cholesterol HR = hazard ratio IR = insulin resistance LDL = low-density-lipoprotein LDL-C = low-density-lipoprotein cholesterol LH = luteinizing hormone PCOS = polycystic ovarian syndrome TGs = triglycerides TZD = thiazolidinedione WHR = waist to hip ratio