Type 2 Diabetes Mellitus, Insulin Resistance, and Vitamin D.

PURPOSE OF REVIEW: There is a growing, largely inconsistent, literature on the role of vitamin D in association with type 2 diabetes, insulin resistance/insulin secretion, glycemic indices, and complications of type 2 diabetes. Pathophysiologic, bystander, preventive, and treatment roles of vitamin D have all been proposed. In this focused review, we attempt to organize and clarify our current information in this area. RECENT FINDINGS: Clinical study interpretation is difficult because of variability in dosage, dosage form, study duration, and populations studied, as well as recently reported normal human polymorphisms in vitamin D synthesis and catabolism, vitamin D-binding protein, and vitamin D receptors in addition to a host of potential epigenetic confounders. Low vitamin D status appears to be associated with type 2 diabetes and most other insulin resistance disorders reported to date. The extraskeletal benefits of supplementation/repletion in these disorders in our species, with a few highlighted exceptions, remain to be established. This focused review attempts to summarize our current knowledge in this burgeoning area through a review of key meta-analyses, observational studies, randomized control trials, and Mendelian randomization studies and will hopefully serve as a guide to indicate future research directions and current best practice.

Previously unreported deletion of CDC73 involving exons 1-13 was detected in a patient with recurrent parathyroid carcinoma.

Parathyroid carcinoma (PC) is a rare malignancy, presenting sporadically or as part of a genetic syndrome. Diagnosis of PC includes the histopathological diagnosis based on capsular, perineural, or vascular invasion or metastasis. High suspicion for malignancy includes hypercalcaemia greater than 14 mg/dL, extremely high serum parathyroid hormone (PTH) levels, as well as large masses. Given the rarity of PC, it is challenging to design clinical trials for newer therapy. Currently, complete initial surgical excision of the tumour in high-risk patients offers the best chance of cure and prolonged disease-free survival in PC. In the absence of definite data, non-surgical therapies such as radiation and chemotherapy are not routinely recommended. For early detection of recurrence; long-term clinical follow-up with interval measurements of serum calcium and PTH is recommended. Localising studies of PC are helpful. Early screening for CDC73 mutation and multidisciplinary treatment by an endocrine/ENT/surgical oncology team is recommended.

Cardiovascular Effects of Different GLP-1 Receptor Agonists in Patients with Type 2 Diabetes.

PURPOSE OF REVIEW: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have positive effects on weight loss, blood pressure, hyperlipidemia, and glycemic control. They exhibit a broad range of effects on the cardiovascular system that are independent of changes in blood glucose. Cardiovascular outcome trials have demonstrated safety of GLP-1 RAs but results for cardiovascular efficacy were varied. The aim of the present review is the assessment of the effects of GLP-1 RAs on cardiovascular risk factors, and major cardiovascular events. RECENT FINDINGS: Use of GLP-1 RAs was associated with relative risk reduction in cardiovascular mortality and all-cause mortality with no significant differences for the incidence of severe hypoglycemia, pancreatitis, pancreatic cancer, or medullary thyroid cancer when compared to placebo. Although there are differences between individual medications with respect to their effects on cardiovascular events, GLP-1 RAs offer a favorable risk-benefit profile. The present review confirms the cardiovascular safety and efficacy vs placebo of GLP-1 RAs in patients with type 2 diabetes at moderate-to-high atherosclerotic cardiovascular risk without significant side effects. Although professional guidelines recommend metformin as the sole first-line agent, GLP-1 RAs can be used as first-line therapy in individuals with type 2 diabetes who either are intolerant to metformin or have high cardiovascular risk factors.

Treatment of Nonclassic 11-Hydroxylase Deficiency with Ashwagandha Root.

An elderly woman presented with acne and male pattern alopecia, which upon diagnostic evaluation was found to be due to nonclassic 11-hydroxylase deficiency. We previously reported that Ashwagandha root ameliorates nonclassic 3-ß-ol dehydrogenase and aldosterone synthase deficiencies. This is the first report of its use being associated with amelioration of nonclassic 11-hydroxylase deficiency, where its apparent effects appear to be dose-related.

Possible ACTH-independent, cortisol-secreting and DHEA-secreting metastatic hepatocellular carcinoma causing Cushing's syndrome.

Cortisol production by hepatocellular carcinoma (HCC) has not been previously reported and dehydroepiandrosterone (DHEA) secretion by HCC is rare. We report a case of a 53-year-old woman admitted with dyspnoea and headache. Serum cortisol by immunoassay (IA) was 42.3 µg/dL, urine free cortisol (UFC) by liquid chromatography mass spectrometry (LC/MS/MS) was 106.1 µg/24 h, serum DHEA by LC/MS/MS was 4886 ng/mL, serum DHEA-S by LC/MS/MS was 4477 ng/mL and plasma adrenocorticotrophic hormone (ACTH) by IA was 10 pg/mL. CT showed likely HCC metastatic to the left adrenal gland, brain and lungs. Liver and adrenal gland biopsies confirmed HCC. ACTH tumour staining was negative. High serum and UFC levels and high serum DHEA and DHEA-S with low-normal plasma ACTH and negative tumour ACTH staining suggested ACTH-independent ectopic Cushing's syndrome (CS); cortisol and DHEA being likely secreted by the HCC. To the best of our knowledge, this is the first reported case of HCC associated with CS.

Hallucinations associated with miglitol use in a patient with chronic kidney disease and hypothyroidism.

A 71-year-old woman with type 2 diabetes mellitus, chronic kidney disease stage IV, primary hypothyroidism and osteoarthritis, whose prescribed treatment included miglitol 50 mg thrice daily with the first bite of meals, reported that she suffered visual hallucinations while taking miglitol, which resolved within a few days of stopping the drug. When she resumed miglitol, hallucinations recurred within a few days and again resolved within a few days of stopping the drug. To our knowledge, this is the first reported case of hallucinations associated with the use of an α-glucosidase inhibitor and highlights a previously unappreciated risk associated with the use of this generally quite benign drug class.

Diabetes and bone health.

The increasing prevalence of diabetes especially type 2 diabetes worldwide is indisputable. Diabetics suffer increased morbidity and mortality, compared to their non-diabetic counterparts, not only because of vascular complications, but also because of an increased fracture incidence. Both types 1 and 2 diabetes and some medications used to treat it are associated with osteoporotic fractures. The responsible mechanisms remain incompletely elucidated. In this review, we evaluate the role of glycemic control in bone health, and the effect of anti-diabetic medications such as thiazolidinediones, sulfonylureas, DPP-4 inhibitors, and GLP-1 agonists. In addition, we examine the possible role of insulin and metformin as anabolic agents for bone. Lastly, we identify the current and future screening tools that help evaluate bone health in diabetics and their limitations. In this way we can offer individualized treatment, to the at-risk diabetic population.

Roux-en-Y gastric bypass in the treatment of non-classic congenital adrenal hyperplasia due to 11-hydroxylase deficiency.

Non-classic adrenal hyperplasia (NCAH) has been associated with insulin resistance (IR). Therapies such as metformin, thiazolidinediones and lifestyle alterations improve IR and also ameliorate the biochemical and clinical abnormalities of NCAH, much as they do in polycystic ovarian syndrome (PCOS). More recently, bariatric surgery, such as Roux-en-Y gastric bypass (RYGBP), has also been associated with improvement in IR and amelioration of PCOS and may, therefore, be beneficial in NCAH. We report a case of a 39-year-old, deaf-mute, obese woman with NCAH due to 11-hydroxylase deficiency who underwent RYGBP followed by improvement of NCAH manifestations. She was initially treated with metformin and pioglitazone, which lowered serum 11-deoxycortisol from 198 ng/dl (<51) to 26 ng/dl. Five weeks after undergoing RYGBP her body mass index fell from 44.18 kg/m(2) to 39.54 kg/m(2) and, despite not taking metformin or pioglitazone, serum 11-deoxycortisol remained normal at <40 ng/dl. Concurrently and subsequently, her NCAH symptoms, for example, alopecia, hirsutism and irregular menses normalised as well. We conclude that RYGBP, like other interventions that reduce IR, may be another way of treating non-classic 11-hydroxylase deficiency in selected patients.

Cardiac tamponade as a presenting manifestation of severe hypothyroidism.

We report a patient who presented to our hospital with unusual symptoms of non-specific complaints and uncontrolled hypertension. Acute cardiac tamponade was suspected from cardiomegaly on routine chest x-ray and confirmed with an echocardiogram. Analysis of the pericardial fluid and other laboratory data ruled out all the common causes except for hypothyroidism as a cause of cardiac tamponade. Tamponade results from increased intrapericardial pressure caused by the accumulation of pericardial fluid. The rapidity of fluid accumulation is a greater factor in the development of tamponade than absolute volume of the effusion. Hypothyroidism is a well-known cause of pericardial effusion. However, tamponade rarely develops owing to a slow rate of accumulation of pericardial fluid. The treatment of hypothyroidic cardiac tamponade is different from other conditions. Thyroxine supplementation is all that is necessary. Rarely, pericardiocentesis is needed in a severely symptomatic patient.

Ashwagandha root in the treatment of non-classical adrenal hyperplasia.

Congenital adrenal hyperplasia (CAH) is a well-characterised family of disorders of the adrenal cortices, resulting in varying degrees of cortisol, aldosterone and androgen deficiency or androgen excess, depending on the enzyme(s) affected and the degree of quantitative or functional enzyme deficit. Withania somnifera (WS), commonly known as Ashwagandha, is a medicinal plant that has been employed for centuries in ayurvedic medicine. Preclinical studies have shown that WS increases circulating cortisol levels and improves insulin sensitivity. We report the case of a 57-year-old woman with non-classical adrenal hyperplasia due to both 3-ß-ol dehydrogenase deficiency and aldosterone synthase deficiency who was self-treated with WS for 6 months. After 6 months of treatment her serum 18-OH-hydroxycorticoserone, 17-OH-pregnenolone, corticosterone and 11-deoxycortisol decreased by 31%, 66%, 69% and 55%, respectively. The biochemical improvement was accompanied by a noticeable reduction in scalp hair loss.

1-α hydroxylation defect in postural orthostatic tachycardia syndrome: remission with calcitriol supplementation.

A 37-year-old woman presented with a history of reactive hypoglycaemia, non-classic adrenal hyperplasia (NCAH), osteopenia and fibromyalgia. After several months of palpitations, postural orthostatic tachycardia syndrome (POTS) was diagnosed by tilt table studies. Her heart rate (HR) reached 191 bpm at 60 degrees from horizontal. Investigation suggested increase in epinephrine and norepinephrine levels in response to tilt table. Her 25(OH) vitamin D level measured by immunoextraction radioimmunoassay was 35 pg/ ml (normal 9-54 pg/ml) while her 1,25(OH)(2) vitamin D3 level was 24 pg/ml (normal 30-67 pg/ml). Accordingly, she was started on calcitriol 0.25 mcg orally daily. At her next visit after 5 months, she reported remarkable improvement in her palpitations and had been working full time for the past 4 months. HR both seated and upright was 72 bpm. After 3 months, her 1,25(OH)(2) vitamin D3 level on calcitriol was 40 pg/ml. The authors suggest that 1-α hydroxylation defects should be sought and treated, if present, with calcitriol in patients with POTS.

Effect of raloxifene in human neurocysticercosis.

The authors report a patient whose polycystic ovarian syndrome (PCOS) and increased calcitriol level were associated with neurocysticercosis (NCC), for which she refused standard therapy. Based upon a report on treatment with tamoxifen in murine cysticercosis,1 she was offered raloxifene. She began raloxifene 60 mg/day on 21 January 2010. On 17 March 2010 she was pregnant, and was terminated on 14 April 2010. MRI 26 April 2010 showed diminution in size, shrinkage and loss of viability in a number of the cysts. Total lesions fell from 37 to 33, 10 lesions shrunk, 5 resolved, 18 were unchanged, 4 enlarged and 1 new lesion developed. Concomitantly serum calcitriol fell from 81 to 41 pg/ml while 25-OH-vitamin D level fell from 34 to 30 ng/ml. Alteration of the hormonal milieu may reduce cestode burden in human NCC. The pregnancy on raloxifene, though unfortunate, supports the concept that NCC caused the PCOS. Serum calcitriol may be a useful biomarker for assessing disease activity in NCC.

Management of type 2 diabetes mellitus in the elderly.

AIM: To provide evidence based recommendations for optimal care diabetes care in the elderly. BACKGROUND: Diabetes affects approximately 25% of the population ≥65 years, and that percentage is increasing rapidly, particularly in minorities who represent an important fraction of the uninsured/underinsured. Diabetes is an important cause of hospital admissions and a co-morbidity in as high as 50% of hospital inpatients. It impacts mortality and quality of life. While tools have become available to improve glycemic control, enthusiasm for their application must be tempered with the sober realization of the risks involved in intensification of glycemic control, chiefly hypoglycemia. METHODS: Weighted review from PubMed and other literature search tools in descending order of randomized control trials, observational studies, pilot studies, published guidelines, the authors' clinical experience, and expert opinion. RESULTS/CONCLUSIONS: • HbA1c targets should be stratified according to the frailty of the elderly diabetic patient: <7.0% in the generally well elderly and < 8.0% in the frail elderly. • Therapies are available that achieve glycemic goals, while minimizing the risk of hypoglycemia, taking into consideration such factors as cognitive function, renal and hepatic function, bone density, fall risk, and hypoglycemia unawareness. • When insulin is used determir or glargine are safer choices than NPH. • Ultra-short acting prandial insulins are safer than regular insulin. • Pen devices for insulin delivery significantly reduce dosing errors and the risk of hypoglycemia. • Sudden managed care formulary changes that disrupt patients' diabetes treatment should be prevented through national policy initiatives. • Up to date home medication lists help prevent dangerous medication errors. • Widespread adoption of telehealth approaches can significantly improve glycemic control and render it safer.

Metformin-responsive classic salt-losing congenital adrenal hyperplasia due to 21-hydroxylase deficiency: a case report.

OBJECTIVE: To study the effect of adding metformin to standard steroid replacement therapy in a patient with classic salt-losing congenital adrenal hyperplasia due to 21-hydroxylase deficiency with suboptimal biochemical and clinical control. METHODS: We present the clinical and laboratory findings before and after the addition of metformin to the therapeutic regimen of the study patient. RESULTS: A 17-year-old girl had been diagnosed as a neonate with classic salt-losing congenital adrenal hyperplasia caused by 21-hydroxylase deficiency (CYP21A2 deficiency). She was treated with hydrocortisone, 20 mg in the morning and 10 mg at bedtime, and fludrocortisone, 50 mcg daily. While on steroid replacement, she maintained normal serum electrolytes, glucose, blood pressure, and external genitalia, but she continued to express clinical features of obesity, hirsutism, amenorrhea, and acanthosis nigricans. Elevated laboratory measurements included the following: fasting 17-hydroxyprogesterone, 3410 ng/dL; total testosterone, 326 ng/dL; and androstenedione, 390 ng/dL. She was initiated on metformin, 500 mg twice daily after meals. After 3 months, the patient lost 2 kg, amenorrhea resolved, 17-hydroxyprogesterone decreased to 1539 ng/dL, total testosterone decreased to 163 ng/dL, and androstenedione levels remained unchanged. CONCLUSIONS: Metformin, an agent known to reduce insulin resistance, further suppressed the 17-hydroxyprogesterone concentration in a patient with classic congenital adrenal hyperplasia on steroid replacement therapy. Metformin may improve clinical and biochemical outcomes in classic congenital adrenal hyperplasia without the risk of iatrogenic Cushing syndrome.

Novel endocrine disrupter effects of classic and atypical antipsychotic agents and divalproex: induction of adrenal hyperandrogenism, reversible with metformin or rosiglitazone.

OBJECTIVE: To ascertain an association between the a priori known insulin resistance caused by antipsychotic agents and divalproex and adrenal hyperandrogenism and to determine whether the associated hyperandrogenism is reversible with insulin sensitizers. METHODS: We studied 26 consecutive psychiatric inpatients (22 women and 4 men) receiving the aforementioned medications, who were referred to us for a consultation. They ranged in age from 19 to 79 years and had a mean body mass index (SEM) of 32.35 +/- 1.26 kg/m2. Between 8 AM and 9 AM, blood samples were collected for 17-hydroxyprogesterone, 17-hydroxypregnenolone, androstenedione, dehydroepiandrosterone (DHEA), DHEA sulfate, 11-deoxycortisol, luteinizing hormone and follicle-stimulating hormone (in reproductive age women), estrone, estradiol (in reproductive age women), free testosterone (in women), deoxycorticosterone, and sex hormone-binding globulin (SHBG), which were measured by radioimmunoassay, after chromatography if necessary. For intact, premenopausal women, measurement of the abnormal steroid metabolite or SHBG level was repeated during prednisone therapy (5 mg at bedtime) to document the likely adrenal origin of the abnormality. Men, women who had undergone bilateral oophorectomy, and postmenopausal women had hyperandrogenism of adrenal origin by default. Clinical features included central obesity, acanthosis, hirsutism, alopecia, type 2 diabetes mellitus, and oligomenorrhea. RESULTS: We found reversed estrone/estradiol ratios in 4 patients, decreased SHBG in 4, increased 17-hydroxy-pregnenolone in 8, increased 17-hydroxyprogesterone in 2, increased deoxycorticosterone in 2, increased DHEA sulfate in 1, increased 11-deoxycortisol in 4, increased androstenedione in 1, and reversed ratios of luteinizin hormone to follicle-stimulating hormone in 2. The bio-chemical abnormalities were corrected in 8 of 8 patients receiving metformin and in 2 of 2 patients receiving rosiglitazone. CONCLUSION: Insulin resistance caused by antipsychotic agents and divalproex is associated with adrenal hyperandrogenism. Metformin and rosiglitazone correct the biochemical abnormalities detected without compromising their psychotropic effect. Adrenal androgen synthesis may be increased by hyperinsulinemia-induced hyperphosphorylation of P450c17 alpha, resulting in an increase in its 17,20-lyase activity, which magnifies the effects of any distal steroidogenic enzyme defects. Treatment with metformin or rosiglitazone prevents excess adrenal androgen synthesis.

Hypertension in patients with Cushing's disease: pathophysiology, diagnosis, and management.

Hypertension is a very common comorbidity in patients with Cushing's disease/syndrome, resulting from the interplay of several pathophysiologic mechanisms, including stimulation of mineralocorticoid and glucocorticoid receptors as well as the associated insulin resistance, sleep apnea, and overexpression of renin-angiotensin system. Although treatment of Cushing's disease results in resolution or amelioration of hypertension in these patients, a significant proportion of patients do not achieve complete cure or require a prolonged period of time for complete response to therapy. Therefore, therapeutic strategies for Cushing's-specific hypertension are necessary to decrease morbidity and mortality associated with this disease. In this review, we discuss the pathophysiology of hypertension in patients with Cushing's disease, highlighting the therapeutic options, including the exciting new developments in the role of peroxisome proliferator-activated receptor (PPAR)-g agonists in the management of this patient population.

Control of blood pressure and other cardiovascular risk factors at different practice settings: outcomes of care provided to diabetic women compared to men.

Cardiovascular disease (CVD) is the major cause of morbidity and mortality in diabetes. To determine the proportion of patients who met the American Diabetes Association guidelines for control of CVD risk factors and to assess the achievement of these guidelines in women compared with men, we conducted a cross-sectional study of 3678 diabetic cohorts followed at seven medical centers, two Veteran Administration hospitals, three urban clinics, and two suburban clinics. Overall, 28% met the target blood pressure of <130/80 mm Hg, 48.8% achieved a goal low-density lipoprotein cholesterol of <100 mg/dL, and 35.8% had hemoglobin A1c of <7%. Gender comparisons of 2788 diabetic patients at urban and suburban centers showed that women had a lower percentage of low-density lipoprotein cholesterol <100 mg/dL (45.8 vs. 51.3, p<0.01) and a lower percentage of screening for retinopathy (54 vs. 60, p<0.01) and nephropathy (37 vs. 49, p<0.01). However, overall there were no gender differences in the percentage of patients who achieved a goal blood pressure <130/80 mm Hg or hemoglobin A1c <7%. Control of blood pressure and other CVD risk factors in diabetic patients was largely suboptimal, especially for diabetic women. These observations underscore the need for better strategies for control of CVD risk in the diabetic population in general, and women in particular.