The effects of cannabis and cannabinoids on the endocrine system.

With the increase in cannabis use due to policy changes and areas of decriminalization, it is important to recognize the potential impact of these substances on endocrine processes. Cannabinoids have many effects by activating the endocannabinoid system. This system plays a role in the normal functioning of nearly every organ and consists of the body's natural endocannabinoids, the cannabinoid receptors, and the enzymes and processes that regulate endocannabinoids. Exogenous cannabinoids such as Δ9-tetrahydrocannabinol (THC) are known to act through cannabinoid type 1 and 2 receptors, and have been shown to mimic endocannabinoid signaling and affect receptor expression. This review summarizes the known impacts of cannabis on thyroid, adrenal, and gonadal function in addition to glucose control, lipids, and bone metabolism, including: reduced female fertility, increased risk of adverse pregnancy outcomes, reduced sperm counts and function, lower thyroid hormone levels with acute use, blunting of stress response with chronic use, increased risk of prediabetes but lower risk of diabetes, suggested improvement of high density lipoproteins and triglycerides, and modest increase in fracture risk. The known properties of endocannabinoids, animal data, population data, and the possible benefits and concerns of cannabinoid use on hormonal function are discussed. The interconnectivity of the endocrine and endocannabinoid systems suggests opportunities for future therapeutic modalities which are an area of active investigation.

Desensitization to Methimazole.

OBJECTIVE: Thionamides (methimazole and propylthiouracil) have been associated with common side effects, such as rash and pruritus, and rare but serious adverse effects, such as agranulocytosis and hepatotoxicity. Methimazole is usually the preferred thionamide for the treatment of hyperthyroidism if the patient is not planning to conceive or not in the first trimester of pregnancy, given the less frequent dosing and lower risk of hepatotoxicity. In patients who experience rash or itching when treated with methimazole, switching them to propylthiouracil is one treatment option. Here we report our experience regarding desensitization to methimazole to allow continued treatment with methimazole as an alternative management option. METHODS: We conducted a retrospective chart review of patients at a single institution who had side effects to methimazole and who were desensitized to methimazole under the supervision of an allergist. A total of 7 patients were included who experienced side effects to methimazole that did not include agranulocytosis or hepatotoxicity. RESULTS: All 7 patients were able to take methimazole for treatment of their hyperthyroidism, either for continued medical therapy or as a bridge to definitive therapy, with either surgery or radioactive iodine treatment. CONCLUSION: Under the supervision of an allergist, desensitization to methimazole is an option for treating patients who experience side effects to methimazole (excluding agranulocytosis and hepatotoxicity).

BIOTIN INTERFERENCE WITH ROUTINE CLINICAL IMMUNOASSAYS: UNDERSTAND THE CAUSES AND MITIGATE THE RISKS.

OBJECTIVE: The objectives of this report are to review the mechanisms of biotin interference with streptavidin/biotin-based immunoassays, identify automated immunoassay systems vulnerable to biotin interference, describe how to estimate and minimize the risk of biotin interference in vulnerable assays, and review the literature pertaining to biotin interference in endocrine function tests. METHODS: The data in the manufacturer's "Instructions for Use" for each of the methods utilized by seven immunoassay system were evaluated. We also conducted a systematic search of PubMed/MEDLINE for articles containing terms associated with biotin interference. Available original reports and case series were reviewed. Abstracts from recent scientific meetings were also identified and reviewed. RESULTS: The recent, marked, increase in the use of over-the-counter, high-dose biotin supplements has been accompanied by a steady increase in the number of reports of analytical interference by exogenous biotin in the immunoassays used to evaluate endocrine function. Since immunoassay methods of similar design are also used for the diagnosis and management of anemia, malignancies, autoimmune and infectious diseases, cardiac damage, etc., biotin-related analytical interference is a problem that touches every area of internal medicine. CONCLUSION: It is important for healthcare personnel to become more aware of immunoassay methods that are vulnerable to biotin interference and to consider biotin supplements as potential sources of falsely increased or decreased test results, especially in cases where a lab result does not correlate with the clinical scenario. ABBREVIATIONS: FDA = U.S. Food & Drug Administration FT3 = free tri-iodothyronine FT4 = free thyroxine IFUs = instructions for use LH = luteinizing hormone PTH = parathyroid hormone SA/B = streptavidin/biotin TFT = thyroid function test TSH = thyroid-stimulating hormone.

SELECTIVE HYPOALDOSTERONISM: A REVIEW.

OBJECTIVE: Selective hypoaldosteronism (SH) is a condition manifested by hyperkalemia due to low aldosterone secretion with normal cortisol. One of the obstacles in diagnosis is the awareness of the condition itself. The objective of this review is to highlight what is known about the epidemiology, pathophysiology, etiology, presentation, diagnosis, and treatment of SH. METHODS: Literature search was performed on PubMed and Ovid Medline for articles which contained hypoaldosteronism as a major topic. RESULTS: The recent literature on this topic is surprisingly limited. Few recent review articles were found, none of which were in English and less than 5 years old. Case reports and genetic literature were also included in this review, as they contain the most recent reports of SH in the literature. CONCLUSION: Awareness about SH will hopefully help physicians to identify patients at risk as well as decide on treatment if any therapy is required.

Neurologic complications of diabetes.

Neuropathy as a complication of diabetes is common and presents in a wide variety of clinical scenarios. Often the work-up is one of exclusion tempered with monitoring the response of symptoms to treatment options. The collaboration of a neurologist is often crucial to determining the best course of action for the patient. This review will address proposed pathogenic mechanisms and potential therapeutic interventions, both pharmacologic and nonpharmacologic.

The association between glycemic control and clinical outcomes after kidney transplantation.

OBJECTIVE: To analyze the relationship between glycemic control after renal transplantation and subsequent graft function and complications. METHODS: We conducted a retrospective chart review of 202 consecutive patients undergoing kidney transplantation to analyze the association between perioperative and chronic glycemic control and clinical outcomes of rejection, infection, and hospital readmission during the first year after kidney transplantation. RESULTS: Mean in-hospital blood glucose (BG) was 157 ± 34.5 mg/dL. Mean hemoglobin A1c (HbA1c) during the first 12 months posttransplantation was 6.84 ± 1.46%. Fiftyfour patients (27%) were treated for acute or chronic rejection, 88 (44%) for infection, and 149 (74%) patients were readmitted at least once within the first year after transplantation. There were no significant differences in the risks for rejection, infection, or readmission across the 5 mean initial inpatient BG or subsequent HbA1c quintiles. In addition, there was no significant relationship between the percentage of BG measurements that fell in the "tight control" range of 80 to 110 mg/dL for each patient and any of the outcomes. CONCLUSION: We did not find an association between glycemic control (perioperative or chronic) and the outcomes of graft rejection, infection, or hospital readmission in the first 12 months after renal transplantation. Our results suggest that "near normal" glycemic targets are not necessary for managing hyperglycemia after renal transplantation.

A psychoeducational intervention (SWEEP) for depressed women with diabetes.

BACKGROUND: Clinically significant depression is present in 25 % of individuals with type 2 diabetes, its risk being doubled in women. PURPOSE: To examine the effectiveness of the Study of Women's Emotions and Evaluation of a Psychoeducational (SWEEP), a group therapy for depression treatment based on cognitive behavioral therapy principles that was developed for women with type 2 diabetes was conducted. METHODS: Women with significantly elevated depression symptoms (Center for Epidemiologic Studies Depression Scale ≥16) were randomized to SWEEP (n = 38) or usual care (UC, n = 36). RESULTS: Multilevel modeling indicated that SWEEP was more effective than UC in reducing depression (mean difference of -15 vs. -7, p < .01), decreasing trait anxiety (mean difference of -15 vs. -5, p < .01), and improving anger expression (mean difference of -12 vs. -5, p < .05). Although SWEEP and UC had improvements in fasting glucose (mean difference of -24 vs. -1 mg/dl) and HbA1c (mean difference of -0.4 vs. -0.1 %), there were no statistically significant differences between groups. CONCLUSIONS: SWEEP was more effective than UC for treating depressed women with type 2 diabetes. Addition of group therapy for depression meaningfully expands the armamentarium of evidence-based treatment options for women with diabetes.

Vitamin D Supplementation for the Treatment of Depressive Symptoms in Women with Type 2 Diabetes: A Randomized Clinical Trial.

Aim: To determine the efficacy and safety of vitamin D3 supplementation in reducing depressive symptoms in women with type 2 diabetes (T2D), depression, and low vitamin D. Methods: In this double-blind randomized active comparator-controlled trial, women with significant depressive symptoms as assessed by the Center for Epidemiologic Studies Depression (CES-D) scale received weekly oral vitamin D3 supplementation (50,000 IU) or an active comparator (5,000 IU) for 6 months. Assessments of vitamin D, 25-hydroxyvitamin D [25 (OH) D], and depression were measured at baseline, 3 months, and 6 months. Results: A total of 129 women were randomized, from which 119 completed the study (57 in lower dose and 62 in higher dose). Participants had an average 25 (OH) D and HbA1c of 20.8 ng/mL and 7.8%, respectively, at baseline. They were diverse (48% Black) and had a mean age of 50 and T2D for about 8 years. Upon completion of vitamin D3 supplementation, serum 25 (OH) D levels increased with 50,000 IU (+34 ng/mL) and 5,000 IU (+10 ng/mL). There was no difference in CES-D scores by treatment dose. Overall, depressive symptoms significantly improved over time with an average CES-D decline of 12.98 points (95% CI: -15.04 to -10.93; p < 0.001). Among women with moderate baseline depressive symptoms, those receiving the lower dose had nominally lower depression scores at follow-up than those in the higher dose cohort. Among women with severe baseline depressive symptoms, the improvement in follow-up depression scores was the same regardless of dose. Conclusions: There was no difference in the dosing effect of vitamin D3 supplementation for the treatment of depressive symptoms in women with T2D who present with significant symptoms and low vitamin D. Regardless of the dose, participants' mood improved over time. Further study of vitamin D to target depressive symptoms in comorbid populations is needed.

Baseline risk markers and visit-to-visit variability in relation to kidney outcomes - A post-hoc analysis of the PERL study.

BACKGROUND: Baseline risk variables and visit-to-visit variability (VV) of systolic blood pressure (SBP), HbA1c, serum creatinine, and uric acid (UA) are potential risk markers of kidney function decline in type 1 diabetes. METHODS: Post-hoc analysis of a double-blind randomized placebo-controlled clinical trial investigating allopurinol's effect on iohexol-derived glomerular filtration rate (iGFR) in type 1 diabetes with elevated UA. Primary outcome was iGFR change over three years. Linear regression with backwards selection of baseline clinical variables was performed to identify an optimized model forecasting iGFR change. Furthermore, VVs of SBP, HbA1c, serum creatinine, and UA were calculated using measurements from the run-in period; thereafter assessed by linear regression, with iGFR change as the dependent variable. RESULTS: 404 participants were included in the primary analyses. In the optimized baseline variable model, higher HbA1c, SBP, iGFR, albuminuria, and heart rate, and mineralocorticoid receptor antagonist prescription were associated with greater iGFR decline. Higher VV of SBP was associated with greater iGFR decline (adjusted ß (ml/min/1.73 m2/50 % increase): -0.79, p = 0.01). CONCLUSIONS: We identified several risk markers for faster iGFR decline in a high-risk population with type 1 diabetes. While further research is needed, our results indicate possible new and clinically feasible measures to risk stratify for DKD in type 1 diabetes.

Applications and pitfalls of hemoglobin A1C and alternative methods of glycemic monitoring.

INTRODUCTION: Intensive glycemic control minimizes the risks of microvascular complications in diabetes. A1C is a convenient estimate of mean blood glucose, but is not the only marker available. The practical use and limitations of alternative markers and continuous glucose monitors are the focus of this review. METHODS: PubMed and the Cochrane Library were searched for studies concerning applications or limitations of A1C, fructosamine, glycated albumin, 1,5-anhydroglucitol, skin autofluorescence, and continuous glucose monitoring. Papers reporting on strengths, limitations, or comparisons of these methods were reviewed for inclusion. RESULTS: A1C reflects three months of glycemic control and is not an ideal marker in all patient populations. Fructosamine and glycated albumin reflect mean blood glucose over three weeks. 1,5-Anhydroglucitol can measure hyperglycemic excursions in days to weeks. Continuous glucose monitors provide immediate feedback for timely intervention to reduce glycemic excursions and can assess glycemic variability. Current barriers to continuous glucose monitor use include inexperience, cost, discomfort, and medication interference. CONCLUSIONS: Many promising alternative glycemic markers exist. The main limitations for all alternative methods of glycemic monitoring are a lack of standardization for clinically useful cut-offs or guidelines, and a lack of long-term data on their association with complications, particularly in varied patient populations.

SARS-CoV-2 (COVID-19) and the Endocrine System.

As SARS-CoV-2 (COVID-19) overtakes the world, causing moderate to severe disease in about 15% of infected patients, COVID-19 is also found to have widespread effects throughout the body with a myriad of clinical manifestations including the endocrine system. This manuscript reviews what is known about the impact of COVID-19 on the pathophysiology and management of diabetes (both outpatient and inpatient) as well as pituitary, adrenal, thyroid, bone, and gonadal function. Findings in this area are evolving, and long-term effects of infection remain an active area of further research.

Thyrotoxicosis-induced cardiomyopathy treated with venoarterial extracorporeal membrane oxygenation.

A 37-year-old woman with no past medical history presented with longstanding untreated hyperthyroidism and consequentially developed thyrotoxicosis-induced cardiomyopathy. Upon admission, she was noted with a heart rate of 172 beats per minute and an EKG consistent with supraventricular tachycardia which was unresponsive to adenosine. Shortly after the initiation of a non-cardioselective beta-blocker for the treatment of persistent tachycardia, she developed profound cardiogenic shock refractory to vasopressors and inotropes. She was diagnosed with thyroid storm, which was ultimately attributed to Graves' Disease and controlled with propylthiouracil, potassium iodide drops, and hydrocortisone. Extracorporeal membrane oxygenation (ECMO) was successfully used as a temporizing measure while her thyroid hormone level normalized and cardiac function recovered. Patients with longstanding untreated hyperthyroidism may be dependent on the induced hyperadrenergic state to compensate for low-output cardiac failure, therefore it is important to exercise caution when initiating beta-adrenergic blockade. Given the expected disease time-course in cases of acute decompensation, ECMO remains a viable option for short-term mechanical circulatory support.

Reducing hyperglycemia hospitalwide: the basal-bolus concept.

BACKGROUND: Hyperglycemia has been identified as potent and independent risk factor for adverse outcomes for patients. An initiative was undertaken to reduce hyperglycemia hospitalwide in adults. METHODS: In a multistep process, insulin protocols were implemented hospitalwide via an electronic provider order entry system. Education regarding basal bolus insulin delivery preceded implementation. Protocols were modified in an ongoing manner on the basis of clinical staff feedback and blood glucose monitoring. Key practice changes included intravenous insulin for initial management in ICU patients, insulin replacement based on the basal bolus approach, elimination of sliding-scale insulin, standardization of blood glucose monitoring before meals, adjustment of prandial dose insulin based on food consumed, administration of prandial dose after the meal, evening snacks ordered based on insulin type, and a glycosolated hemoglobin (A1C) determination for patients with admission glucose > 180 mg/dL. Median inpatient glucose levels in patients with diabetes were assessed using statistical process control methodology. RESULTS: Between January 2004 and September 2007, median glucose for all inpatients with diabetes decreased 15% from 159 mg/dL to < 135 mg/dL. The percentage of inpatients with diabetes who experienced a day with a glucose measurement above 180 mg/dl decreased from 66% to 53%. Frequency of hypoglycemia (< 60 mg/dL) did not change following protocol implementation. DISCUSSION: Major improvements in hospitalwide blood glucose control are feasible and safe, employing standard protocols based on the basal-bolus concept. Improvement was sustained during a four-year period with ongoing institutional support, multidisciplinary education, collaboration between clinical services, and monitoring of clinical outcomes on a quarterly basis.

Vitamin D Supplementation and Cognition in People with Type 2 Diabetes: A Randomized Control Trial.

AIM: Type 2 diabetes increases the risk of cognitive decline which adversely impacts self-management of the disease. Evidence also supports a relationship between low serum 25(OH)D levels and poor cognition. The purpose of this trial was to assess vitamin D supplementation on cognitive executive functioning in persons living with type 2 diabetes. METHODS: This was a double-blinded RCT where participants were randomized to receive either weekly vitamin D3 supplementation (50,000 IUs) or a matching comparator (5,000 IUs) for three months. The primary outcome was a battery of neuropsychological tests. Serum 25(OH)D was measured by liquid chromatography/tandem mass spectrometry. Repeated assessments of cognitive measures were collected over 12 weeks using alternative testing forms to minimize practice effects. RESULTS: Thirty participants were randomized to either the low-dose allocation (n = 15) or the high-dose allocation (n = 15). Most participants were female (83%) and identified as Black (57%). For all cognition measures, there was no statistically significant finding between participants who received high-dose vitamin D supplementation and those who received low-dose supplementation. However, when assessing cognitive function in both groups over time, minimal improvement on the Symbol-Digits, the Stroop Interference Test, and the Trail Making Test Part B was observed. CONCLUSIONS: To our knowledge, this is the first randomized control trial to examine the effects of vitamin D supplementation on cognitive function in people with type 2 diabetes. However, no significant differences in cognitive outcomes between participants who received high-dose therapy and those who received low dose were found.

Vitamin D and diabetes: let the sunshine in.

Diabetes is a leading cause of cardiovascular disease. Persons with diabetes are at greater risk for early cardiac mortality, and for repeat events if they survive their first cardiac event. Recently, low serum concentrations of vitamin D have been associated with increased risk for cardiac events. Evidence indicates that persons with diabetes have lower serum concentrations of vitamin D. In addition, persons at risk for diabetes or metabolic syndrome have inadequate serum concentrations of vitamin D. This review will assess the evidence relative to the impact of vitamin D in the development of diabetes, metabolic syndrome, and diabetes complications. Studies that address vitamin D and its impact on metabolic outcomes as well as possible mechanisms of action are provided. Finally, the assessment and suggested treatment for vitamin D deficiency is addressed. Effective detection and treatment of inadequate vitamin D concentrations in persons with diabetes or those at risk for diabetes may be an easy and cost-effective therapy which could improve their long-term health outcomes as well as their quality of life.

Vitamin D Supplementation Improves Mood in Women with Type 2 Diabetes.

OBJECTIVE: The aim of this study was to determine the effect of vitamin D supplementation on improving mood (depression and anxiety) and health status (mental and physical) in women with type 2 diabetes mellitus (T2DM). METHODS: Fifty women with T2DM and significant depressive symptomology were enrolled into the "Sunshine Study," where weekly vitamin D supplementation (ergocalciferol, 50,000 IU) was given to all participants for six months. The main outcomes included (1) depression (Center for Epidemiologic Studies Depression, CES-D, and Patient Health Questionnaire, PHQ-9), (2) anxiety (State-Trait Anxiety), and (3) health status (Short Form, SF-12). RESULTS: Forty-six women (92%) completed all visits. There was a significant decrease in depression (CES-D and PHQ-9, p < 0.001) and anxiety (state and trait, p < 0.001). An improvement in mental health status (SF-12, p < 0.001) was also found. After controlling for covariates (race, season of enrollment, baseline vitamin D, baseline depression (PHQ-9), and body mass index), the decline in depression remained significant (CES-D, p < 0.001). There was a trend for a better response to supplementation for women who were not taking medications for mood (antidepressants or anxiolytics) (p = 0.07). CONCLUSIONS: Randomized trials to confirm that vitamin D supplementation can improve mood and health status in T2DM women are needed.

A primer on concentrated insulins: what an internist should know.

The common insulin concentration in most preparations of insulin is 100 units per mL or U-100. Human regular U-500 insulin was the first concentrated insulin introduced and it has been available in the United States since the 1950s. Humulin R is the only human regular U-500 available on the market. Human regular U-500 is five times more concentrated than U-100 and because of its pharmacodynamic properties, works as both a basal and a bolus insulin. Human regular U500 allows for delivery of a larger insulin dose with a smaller volume leading to better absorption compared to U-100 and has traditionally been used in patients with moderate to severe insulin resistance. More recently other forms of concentrated insulin have become available and the newer concentrated insulin preparations can be used in diabetic patients with or without insulin resistance. Our intent is to provide primary care physicians with a review of the pharmacology and current literature on concentrated insulins as well as recommendations for patient selection, dose initiation, and dose adjustment.

Ethanol-induced alterations in Rab proteins: possible implications for pituitary dysfunction.

Chronic exposure of pubertal male rats to ethanol results in a decline in serum testosterone, increased gonadotropins, pituitary luteinizing hormone (LH) and follicle stimulating hormone (FSH) content, and decreased or inappropriately normal serum LH and FSH levels, suggesting impaired secretory release of gonadotropins. The molecular mechanisms behind this disorder are undefined, but a disruption of vesicle-mediated secretory processes is possible because intracellular protein trafficking pathways are involved in secretion of glycoproteins such as FSH and LH. Because small GTP-binding proteins of Rab family have been implicated as key regulators of membrane and protein trafficking in mammalian cells, this study was designed to test if ethanol-impaired pituitary FSH and LH secretion is associated with changes in Rab proteins, particularly Rab1B, Rab3B, Rab6, and Rab11. Male Sprague-Dawley rats 35 days old were pair-fed a Lieber-DeCarli diet with ethanol or without ethanol for 5 to 60 days. After ethanol exposure, serum testosterone levels decreased while LH and FSH were inappropriately unchanged. Immunohistochemical staining showed decreased Rab1B, Rab3B, and Rab11 protein levels in ethanol-treated pituitaries. Immunoblotting showed that ethanol induced a transient reduction in Rab6 after 5 days of ethanol exposure, whereas Rab3B decreased after 20 days, Rab11 after 30 days, and Rab1B after 60 days. Despite these changes in Rab proteins, mRNA levels were unaffected by ethanol exposure. We concluded that reductions in key Rab proteins may lead to altered vesicle trafficking and may play a role in disruption of pituitary FSH and LH secretion caused by ethanol.