Evaluating the effectiveness of combined T4 and T3 therapy or desiccated thyroid versus T4 monotherapy in hypothyroidism: a systematic review and meta-analysis.

BACKGROUND: Persistent symptoms in hypothyroid patients despite normalized TSH levels suggest the need for alternative treatments. This study aims to evaluate the effectiveness of combined T4 and T3 therapy or desiccated thyroid (DTE) compared to T4 monotherapy, with a focus on thyroid profile, lipid profile, and quality of life metrics. METHODS: We conducted a systematic review in Embase, Medline/PubMed, and Web of Science up to 11/23/2023. We used the following keywords: "Armour Thyroid," OR "Thyroid extract," OR "Natural desiccated thyroid," OR "Nature-Throid," "desiccated thyroid," OR "np thyroid," OR "Synthroid," OR "levothyroxine," OR "Liothyronine," "Cytomel," OR "Thyroid USP," OR "Unithroid." AND "hypothyroidism. " We only included RCTs and excluded non-RCT, case-control studies, and non-English articles. RESULTS: From 6,394 identified records, 16 studies qualified after screening and eligibility checks. We included two studies on desiccated thyroid and 15 studies on combined therapy. In this meta-analysis, combination therapy with T4 + T3 revealed significantly lower Free T4 levels (mean difference (MD): -0.34; 95% CI: -0.47, -0.20), Total T4 levels (mean difference: -2.20; 95% CI: -3.03, -1.37), and GHQ-28 scores (MD: -2.89; 95% CI: -3.16, -2.63), compared to T4 monotherapy. Total T3 levels were significantly higher in combined therapy (MD: 29.82; 95% CI: 22.40, 37.25). The analyses demonstrated moderate to high heterogeneity. There was no significant difference in Heart Rate, SHBG, TSH, Lipid profile, TSQ-36, and BDI Score. Subjects on DTE had significantly higher serum Total T3 levels (MD: 50.90; 95% CI: 42.39, 59.42) and significantly lower serum Total T4 (MD: -3.11; 95% CI: -3.64, -2.58) and Free T4 levels (MD: -0.50; 95% CI: -0.57, -0.43) compared to T4 monotherapy. Moreover, DTE treatment showed modestly higher TSH levels (MD: 0.49; 95% CI: 0.17, 0.80). The analyses indicated low heterogeneity. There was no significant difference in Heart Rate, SHBG, Lipid profile, TSQ-36, GHQ-28, and BDI Score. CONCLUSIONS: Our study revealed that combined therapy and DTE lead to higher T3 and lower T4 levels, compared to T4 monotherapy in hypothyroidism. However, no significant effects on heart rate, lipid profile, or quality of life were noted. Given the heterogeneity of results, personalized treatment approaches are recommended.

Glucagon-like peptide-1 receptor agonists as a possible intervention to delay the onset of type 1 diabetes: A new horizon.

Type 1 diabetes (T1D) is a chronic autoimmune condition that destroys insulin-producing beta cells in the pancreas, leading to insulin deficiency and hyper-glycemia. The management of T1D primarily focuses on exogenous insulin replacement to control blood glucose levels. However, this approach does not address the underlying autoimmune process or prevent the progressive loss of beta cells. Recent research has explored the potential of glucagon-like peptide-1 receptor agonists (GLP-1RAs) as a novel intervention to modify the disease course and delay the onset of T1D. GLP-1RAs are medications initially developed for treating type 2 diabetes. They exert their effects by enhancing glucose-dependent insulin secretion, suppressing glucagon secretion, and slowing gastric emptying. Emerging evidence suggests that GLP-1RAs may also benefit the treatment of newly diagnosed patients with T1D. This article aims to highlight the potential of GLP-1RAs as an intervention to delay the onset of T1D, possibly through their potential immunomodulatory and anti-inflammatory effects and preservation of beta-cells. This article aims to explore the potential of shifting the paradigm of T1D management from reactive insulin replacement to proactive disease modification, which should open new avenues for preventing and treating T1D, improving the quality of life and long-term outcomes for individuals at risk of T1D.

Suicide Attempt With Levothyroxine Overdose.

Symptoms of levothyroxine overdose may vary depending on age, metabolism, etc. There are no specific guidelines for treating levothyroxine poisoning. Here, we present the case of a 69-year-old man with a history of panhypopituitarism, hypertension, and end-stage renal disease who attempted suicide by ingesting 60 tablets of 150 µg levothyroxine (9 mg). Upon presentation to the emergency room, he was asymptomatic despite the free thyroxine level above the range of the assay. During the hospital stay, he developed sinus tachycardia, which was controlled with propranolol. Mild elevations in liver enzymes were also noted. He received stress-dose steroids; hemodialysis was performed a day earlier, and cholestyramine was administered. Thyroid hormone levels started to improve by day seven and finally normalized in 20 days, after which the home dose of levothyroxine was resumed. The human body has several mechanisms to compensate for levothyroxine toxicity, including the conversion of excess levothyroxine to inactive reverse triiodothyronine, increased binding to thyroid-binding globulin, and hepatic metabolism. This case shows that it is possible to have no symptoms even with an overdose of up to 9 mg a day of levothyroxine. Signs and symptoms of levothyroxine toxicity may not appear for several days after ingestion, and, therefore, close observation preferably on a telemetry floor is recommended until the thyroid hormone levels start to decrease. Effective treatment options include beta-blockers preferably propranolol, early gastric lavage, cholestyramine, and glucocorticoids. While hemodialysis has a limited role, antithyroid drugs and activated charcoal are ineffective.

Improving the residual risk of renal and cardiovascular outcomes in diabetic kidney disease: A review of pathophysiology, mechanisms, and evidence from recent trials.

Based on global estimates, almost 10% of adults have diabetes, of whom 40% are estimated to also have chronic kidney disease (CKD). Almost 2 decades ago, treatments targeting the renin-angiotensin system (RAS) were shown to slow the progression of kidney disease. More recently, studies have reported the additive benefits of antihyperglycaemic sodium-glucose co-transporter-2 inhibitors in combination with RAS inhibitors on both CKD progression and cardiovascular outcomes. However, these recent data also showed that patients continue to progress to kidney failure or die from kidney- or cardiovascular-related causes. Therefore, new agents are needed to address this continuing risk. Overactivation of the mineralocorticoid (MR) receptor contributes to kidney inflammation and fibrosis, suggesting that it is an appropriate treatment target in patients with diabetes and CKD. Novel, selective non-steroidal MR antagonists are being studied in these patients, and the results of two large recently completed clinical trials have shown that one such treatment, finerenone, significantly reduces CKD progression and cardiovascular events compared with standard of care. This review summarizes the pathogenic mechanisms of CKD in type 2 diabetes and examines the potential benefit of novel disease-modifying agents that target inflammatory and fibrotic factors in these patients.

Dapagliflozin reduces systolic blood pressure and modulates vasoactive factors.

AIM: To investigate the mechanisms underlying improvements in blood pressure (BP) and congestive heart failure outcomes following treatment with dapagliflozin, a sodium-glucose co-transporter-2 inhibitor. RESEARCH DESIGN AND METHODS: A total of 52 patients with type 2 diabetes (T2D) with an HbA1c of less than 8% participated in this prospective, double-blind and placebo-controlled study. Patients were randomized (1:1) to either dapagliflozin 10 mg daily or placebo for 12 weeks. Half the patients were also monitored for 6 h following their first dose for acute effects on BP. Blood and urine samples were collected and levels of angiotensinogen, angiotensin II, renin, aldosterone, endothelin-1, atrial natriuretic peptide (ANP), brain natriuretic peptide, cyclic adenosine monophosphate, cyclic guanosine monophosphate (cGMP) and neprilysin were measured. The expression of angiotensin-converting enzyme, guanylate cyclase and phosphodiesterase 5 (PDE5) was measured in circulating mononuclear cells (MNC). RESULTS: A total of 24 and 23 patients receiving dapagliflozin and placebo, respectively, completed the 12-week study. Systolic BP decreased significantly, compared with placebo, both after single-dose (by 7 ± 3 mmHg) and 12-week (by 7 ± 2 mmHg) treatment with dapagliflozin. Dapagliflozin suppressed angiotensin II and angiotensinogen (by 10.5 ± 2.1 and 1.45 ± 0.42 µg/mL, respectively) and increased ANP and cGMP (by 34 ± 11 and 29 ± 11 pmol/mL, respectively) compared with the placebo group. cGMP levels also increased acutely following a single dose of dapagliflozin. Dapagliflozin also suppressed PDE5 expression by 26% ± 11% in MNC. There were no changes observed in the other vasoactive mediators investigated. CONCLUSIONS: Dapagliflozin administration in T2D resulted in both acute and chronic reduction in systolic BP, a reduction in vasoconstrictors and an increase in vasodilators. These changes may potentially contribute to its antihypertensive effects and its benefits in congestive cardiac failure.

Liraglutide hospital discharge trial: A randomized controlled trial comparing the safety and efficacy of liraglutide versus insulin glargine for the management of patients with type 2 diabetes after hospital discharge.

AIM: To compare a glucagon-like peptide-1 receptor agonist with basal insulin at hospital discharge in patients with uncontrolled type 2 diabetes in a randomized clinical trial. METHODS: A total of 273 patients with glycated haemoglobin (HbA1c) 7%-10% (53-86 mol/mol) were randomized to liraglutide (n = 136) or insulin glargine (n = 137) at hospital discharge. The primary endpoint was difference in HbA1c at 12 and 26 weeks. Secondary endpoints included hypoglycaemia, changes in body weight, and achievement of HbA1c <7% (53 mmol/mol) without hypoglycaemia or weight gain. RESULTS: The between-group difference in HbA1c at 12 weeks and 26 weeks was -0.28% (95% CI -0.64, 0.09), and at 26 weeks it was -0.55%, (95% CI -1.01, -0.09) in favour of liraglutide. Liraglutide treatment resulted in a lower frequency of hypoglycaemia <3.9 mmol/L (13% vs 23%; P = 0.04), but there was no difference in the rate of clinically significant hypoglycaemia <3.0 mmol/L. Compared to insulin glargine, liraglutide treatment was associated with greater weight loss at 26 weeks (-4.7 ± 7.7 kg vs -0.6 ± 11.5 kg; P < 0.001), and the proportion of patients with HbA1c <7% (53 mmol/mol) without hypoglycaemia was 48% versus 33% (P = 0.05) at 12 weeks and 45% versus 33% (P = 0.14) at 26 weeks in liraglutide versus insulin glargine. The proportion of patients with HbA1c <7% (53 mmol/mol) without hypoglycaemia and no weight gain was higher with liraglutide at 12 (41% vs 24%, P = 0.005) and 26 weeks (39% vs 22%; P = 0.014). The incidence of gastrointestinal adverse events was higher with liraglutide than with insulin glargine (P < 0.001). CONCLUSION: Compared to insulin glargine, treatment with liraglutide at hospital discharge resulted in better glycaemic control and greater weight loss, but increased gastrointestinal adverse events.

The side effects of immune checkpoint inhibitor therapy on the endocrine system.

Immune checkpoint inhibitors (ICIs) are a relatively newer class of drugs approved for the treatment of malignancies such as melanoma, renal, bladder and lung cancer. Immune-related adverse events (IrAEs) involving the endocrine system are a common side effect of these drugs. The spectrum of endocrine adverse events varies by the drug class. Cytotoxic T-lymphocyte-associated antigen-4 inhibitors commonly cause hypophysitis/hypopituitarism, whereas the incidence of thyroid disease is higher with programmed cell death (PD)-1/ ligand (PD-L) protein 1 inhibitors. The focus of this review is to describe the individual endocrinopathies with their possible mechanisms, signs and symptoms, clinical assessment and disease management. Multiple mechanisms of IrAEs have been described in literature including type II/IV hypersensitivity reactions and development of autoantibodies. Patients with pre-existing autoimmune endocrine diseases can have disease exacerbation following ICI therapy rather than de novo IrAEs. Most of the endocrinopathies are relatively mild, and timely hormone replacement therapy allows continuation of ICIs. However, involvement of the pituitary-adrenal axis could be life-threatening if not recognized. Corticosteroids are helpful when the pituitary-adrenal axis is involved. In cases of severe endocrine toxicity (grade 3/4), ICIs should be temporarily discontinued and can be restarted after adequate hormonal therapy. Endocrinologists and general internists need to be vigilant and maintain a high degree of awareness for these adverse events.

Confirmed Hypoglycemia Without Whipple Triad: A Rare Case of Hyper-Warburgism.

Spontaneous hypoglycemia in nondiabetic patients poses a diagnostic challenge. Hypoglycemia in malignancy has several etiologies; an extremely rare mechanism is the Warburg effect causing excess lactate production and avid glucose consumption. We describe the clinical course of a 52-year-old man admitted for chest wall mass and severe but asymptomatic hypoglycemia. Laboratory workup was obtained for insulin vs noninsulin-mediated hypoglycemia, and biopsy of the chest wall mass and 18 F-fluorodeoxyglucose positron emission tomography/computed tomography ( 18 F-FDG-PET/CT) scan were performed. D10 infusion and intravenous/oral steroids started for severe hypoglycemia. Chemotherapy was initiated after biopsy, and blood glucose (BG) and lactate levels followed with clinical response in tumor size and changes in PET/CT. Investigations were significant for venous BG in the 40s (Ademolus Classification of Hypoglycemia grade 2 hypoglycemia), plasma insulin of less than 2 µU/mL (2-20 µU/mL), C-peptide of 0.2 ng/mL (0.8-6.0 ng/mL), insulin-like growth factor 2 (IGF-2) of 113 ng/mL (333-967 ng/mL), serum lactate of 16 mmol/L (0.5-2 mmol/L), and albumin of 2.3 g/dL (3.4-5.4 g/dL). Biopsy showed diffuse large B-cell lymphoma, and PET revealed highly FDG-avid disease in the chest, abdomen, and pelvis, but no FDG uptake was seen in the brain. Hypoglycemia and lactic acidosis improved remarkably after chemotherapy. PET/CT at 4 weeks showed complete metabolic response with reappearance of physiological FDG uptake in the brain. Noninsulin-mediated hypoglycemia was likely due to the combination of profound malnutrition and rapid glucose use by cancer cells. The patient presented with exaggerated Warburg effect (hyper-Warburgism), evident by extreme glucose consumption, severe lactic acidosis, and large tumor burden on PET/CT. Absence of cognitive symptoms was probably due to use of lactate by the brain. Chemotherapy corrected these abnormalities rapidly, and must be instituted in a timely manner.

Liraglutide treatment in overweight and obese patients with type 1 diabetes: A 26-week randomized controlled trial; mechanisms of weight loss.

AIM: To investigate the effects of liraglutide treatment on glycaemic control and adipose tissue metabolism in overweight and obese people with type 1 diabetes (T1DM). RESEARCH DESIGN AND METHODS: A total of 84 adult overweight and obese patients with T1DM, with no detectable C-peptide, were randomized (1:1) to either placebo or 1.8 mg/d liraglutide for 6 months. Blood samples were collected at 0, 12 and 26 weeks. Subcutaneous adipose tissue biopsies, a high-calorie high-fat meal challenge test, continuous glucose monitoring, dual-energy X-ray absorptiometry and MRI were performed before and at the end of treatment. RESULTS: In all, 37 and 27 patients who received liraglutide and placebo, respectively, completed the study. Glycated haemoglobin fell by 0.41 ± 0.18% (4.5±1.4 mmol/mol) from baseline after liraglutide treatment (P = 0.001), and by 0.29 ± 0.19% (3.1±2.0 mmol/mol) compared to placebo (P = 0.1). There was no increase in hypoglycaemia, while the time spent in normal glycaemia increased (P = 0.015) and time spent in hyperglycaemia decreased (P = 0.019). Body weight fell significantly in the liraglutide group, mostly in the form of fat mass loss (including visceral fat), with no change in lean mass. Systolic blood pressure (SBP) also fell after liraglutide treatment. Liraglutide also caused a significant increase in the expression of adipose tissue triglyceride lipase, carnitine palmitoyl transferase-1, peroxisome proliferator-activated receptor (PPAR)α, PPARδ, uncoupling protein-2 and type 2 iodothyronine deiodinase in the adipose tissue. CONCLUSIONS: Liraglutide improves glycaemia, reduces adiposity and SBP. Liraglutide also stimulates mechanisms involved with an increase in lipid oxidation and thermogenesis, while conserving lean body mass.

Dapagliflozin Suppresses Hepcidin And Increases Erythropoiesis.

CONTEXT: Dapagliflozin and other SGLT2 inhibitors are known to increase hematocrit, possibly due to its diuretic effects and hemoconcentration. OBJECTIVE: Since type 2 diabetes is a proinflammatory state and since hepcidin, a known suppressor of erythropoiesis, is increased in proinflammatory states, we investigated the possibility that dapagliflozin suppresses hepcidin concentrations and thus increases erythropoiesis. DESIGN: Prospective, randomized, and placebo-controlled study. SETTING: Single endocrinology center. PATIENTS: Fifty-two obese type 2 diabetes patients. INTERVENTION: Patients were randomized (1:1) to either dapagliflozin (10 mg daily) or placebo for 12 weeks. Blood samples were collected before and after treatments and serum, plasma, and mononuclear cells (MNC) were prepared. MAIN OUTCOME MEASURE: Hepcidin and other hematopoietic factors. RESULTS: Following dapagliflozin treatment, there was a significant fall in HbA1c and a significant increase in hemoglobin concentration and hematocrit. Dapagliflozin treatment significantly reduced circulating hepcidin and ferritin concentrations while causing a significant increase in levels of the hepcidin inhibitor, erythroferrone, and a transient increase in erythropoietin. Additionally, dapagliflozin increased plasma transferrin levels and expression of transferrin receptors 1 and 2 in MNC, while there was no change in the expression of the iron cellular transporter, ferroportin. Dapagliflozin treatment also caused a decrease in hypoxia-induced factor-1α expression in MNC while it increased the expression of its inhibitor, prolyl hydroxylase-2. There were no significant changes in any of these indices in the placebo group. CONCLUSIONS: We conclude that dapagliflozin increases erythropoiesis and hematocrit through mechanisms that involve the suppression of hepcidin and the modulation of other iron regulatory proteins.

Testosterone Increases the Expression and Phosphorylation of AMP Kinase α in Men With Hypogonadism and Type 2 Diabetes.

CONTEXT: Adenosine 5'-monophosphate-activated protein kinase-α (AMPKα) is a mediator of exercise-induced glucose uptake in skeletal muscle. OBJECTIVE: We evaluated whether AMPKα expression and phosphorylation are reduced in skeletal muscle and adipose tissue of patients with hypogonadotropic hypogonadism (HH), and whether testosterone replacement therapy results in restoration of the expression and phosphorylation of AMPKα. DESIGN: This is a secondary analysis of a previously completed trial that showed an insulin-sensitizing effect of testosterone therapy in men with type 2 diabetes and HH. SETTING: Clinical research center at university. PATIENTS: Thirty-two men with HH and 32 eugonadal men were compared at baseline. INTERVENTIONS: Men with HH were treated with intramuscular injections of testosterone or placebo every 2 weeks for 22 weeks. Quadriceps muscle biopsies and subcutaneous abdominal fat biopsies were obtained before and after 4-hour euglycemic hyperinsulinemic clamp, prior to and after testosterone or placebo therapy. OUTCOME MEASURES AND RESULTS: mRNA expression of AMPKα in hypogonadal men was lower by 37% in adipose tissue and 29% in skeletal muscle, respectively, compared with levels in eugonadal men, while phosphorylated AMPKα was lower by 22% and 28%, respectively. Following testosterone replacement, the expression of AMPKα did not alter in the fasting state but increased markedly by 41% and 46% in adipose tissue and muscle, respectively, after the clamp. In contrast, phosphorylated AMPKα increased by 69% in muscle after testosterone therapy but did not change following the clamp. CONCLUSIONS: Testosterone modulates the expression of AMPKα and phosphorylated AMPKα. These effects may contribute to the improved insulin sensitivity following testosterone therapy.

Acute effects of insulin on skeletal muscle growth and differentiation genes in men with type 2 diabetes.

AIMS: Insulin has anabolic effects on skeletal muscle. However, there is limited understanding of the molecular mechanisms underlying this effect in humans. We evaluated whether the skeletal muscle expression of satellite cell activator fibroblast growth factor 2 (FGF2) and muscle growth and differentiation factors are modulated acutely by insulin during euglycemic-hyperinsulinemic clamp (EHC). DESIGN AND METHODS: This is a secondary investigation and analysis of samples obtained from a previously completed trial investigating the effect of testosterone replacement in males with hypogonadotropic hypogonadism and type 2 diabetes. Twenty men with type 2 diabetes underwent quadriceps muscle biopsies before and after 4 h of EHC. RESULTS: The infusion of insulin during EHC raised the expression of myogenic growth factors, myogenin (by 72 ± 20%) and myogenin differentiation protein (MyoD; by 81 ± 22%). Insulin reduced the expression of muscle hypertrophy suppressor, myogenic regulatory factor 4 (MRF4) by 34 ± 14%. In addition, there was an increase in expression of FGF receptor 2, but not FGF2, following EHC. The expression of myostatin did not change. CONCLUSIONS: Insulin has an acute potent effect on expression of genes that can stimulate muscle differentiation and growth.

Increase in Osteocalcin Following Testosterone Therapy in Men With Type 2 Diabetes and Subnormal Free Testosterone.

CONTEXT: One-third of men with type 2 diabetes have subnormal free testosterone concentrations. We evaluated the following: (i) whether bone mineral density (BMD) and bone strength are affected by gonadal status in type 2 diabetes and (ii) the effect of testosterone replacement on markers of osteoblast and osteoclast activity. DESIGN: This is a secondary analysis of a previously completed, randomized, placebo-controlled trial. Ninety-four men with type 2 diabetes were recruited; 44 had subnormal free testosterone concentrations. Men with subnormal free testosterone concentrations were randomized to receive intramuscular injections of testosterone or placebo every 2 weeks for 22 weeks. Dual energy X-ray absorptiometry scans were performed at baseline and at 23 weeks. RESULTS: Men with subnormal free testosterone had similar BMD compared with men with normal free testosterone. However, bone strength indices were lower in men with subnormal free testosterone. BMD was related to free estradiol concentrations (r = 0.37, P = 0.004 at hip), whereas bone strength was related to free testosterone concentrations (r = 0.41, P < 0.001). Testosterone replacement increased osteocalcin concentrations [mean change (95% CI), 3.52 (0.45, 6.59), P = 0.008]. C-Terminal telopeptide (CTx) concentrations also increased at 15 weeks but reverted to baseline following that. There were no changes in other bone turnover markers or BMD. CONCLUSION: We conclude that testosterone replacement resulted in an increase in osteocalcin and a transient increase in CTx, indicating an increase in osteoblastic activity and transient increase in bone breakdown. Therefore, a major action of testosterone is to increase bone turnover in men with type 2 diabetes.

Effect of Testosterone on FGF2, MRF4, and Myostatin in Hypogonadotropic Hypogonadism: Relevance to Muscle Growth.

CONTEXT: Fibroblast growth factor (FGF)2 is an important stimulatory modulator of satellite cells in skeletal muscle. Satellite cells play a cardinal role in muscle growth and repair. OBJECTIVE: We evaluated whether skeletal muscle expression of FGF2 and muscle growth and differentiation factors are reduced in patients with hypogonadotropic hypogonadism (HH) and whether testosterone replacement therapy results in their restoration. DESIGN: This is a secondary analysis of a previously completed trial of testosterone replacement in men with type 2 diabetes and HH. SETTING: Clinical Research Center at a university. PATIENTS: Twenty-two men with HH and 20 eugonadal men were compared at baseline. INTERVENTIONS: Twelve men with HH were treated with intramuscular injections of 250 mg testosterone every 2 weeks for 22 weeks, and 10 men received placebo injections. Quadriceps muscle biopsies and blood samples were obtained before and after testosterone therapy. OUTCOME MEASURES AND RESULTS: The expression of FGF2 and FGF receptor (FGFR)2 in skeletal muscle of men with HH was significantly lower than that in eugonadal men by 57% and 39%, respectively (P < 0.05). After 22 weeks of testosterone, the expression of FGF2 increased, whereas that of myogenic regulatory factor (MRF)4 and myostatin decreased significantly. There was no change in expression of FGFR2, myogenin, or myogenic differentiation protein in the skeletal muscle. Plasma FGF2 and IGF-1 concentrations increased after testosterone therapy. CONCLUSIONS: These data show that testosterone is a major modulator of FGF2, MRF4, and myostatin expression in skeletal muscle. These effects may contribute to the increase in muscle mass after testosterone therapy.

Targeting inflammation to reduce ASCVD in type 2 diabetes.

ASCVD is the leading cause of mortality in T2DM. Inflammation appears to be pivotal in the genesis of ASCVD. As T2DM is also a pro-inflammatory state, our aim was to determine the benefit of anti-inflammatory strategies on ASCVD in T2DM. PubMed searches were conducted using the keywords of T2DM, ASCVD, Inflammation and clinical trials. Our data review suggests that the Mediterranean diet, GLP1 receptor agonists and a monoclonal antibody against IL-1 reduces ASCVD events in T2DM. The former 2 therapies appear to be safe. Anti-IL-1 therapy resulted in an increase mortality from infections. We conclude that only the Mediterranean diet and GLP1 receptor agonists can be safely incorporated into mainstay therapy for patients with T2DM to reduce ASCVD. Further studies are required with respect to biologics targeting Inflammation to establish benefit to risk ratio.

Severe Symptomatic Hypocalcemia from HIV Related Hypoparathyroidism.

We report the case of a 54-year-old Caucasian female who presented with a two-year history of persistent hypocalcemia requiring multiple hospitalizations. Her medical history was significant for HIV diagnosed four years ago. She denied any history of prior neck surgery or radiation. Her vital signs were stable with an unremarkable physical exam. Pertinent medications included calcium carbonate, vitamin D3, calcitriol, efavirenz, emtricitabine, tenofovir disoproxil, hydrochlorothiazide, and inhaled budesonide/formoterol. Laboratory testing showed total calcium of 5.7 mg/dL (normal range: 8.4-10.2 mg/dL), ionized calcium of 2.7 mg/dL (normal range: 4.5-5.5 mg/dL), serum phosphate of 6.3 mg/dL (normal range: 2.7-4.5 mg/dL), and intact PTH of 7.6 pg/mL (normal range: 15-65 pg/mL). She was diagnosed with primary hypoparathyroidism. Anti-calcium-sensing receptor antibodies and NALP5 antibodies were tested and found to be negative. During subsequent clinic visits, doses of calcium supplements and calcitriol were titrated. Last corrected serum calcium level was 9.18 mg/dL. She was subsequently lost to follow-up. This case gives insight into severe symptomatic hypocalcemia from primary hypoparathyroidism attributed to HIV infection. We suggest that calcium levels should be closely monitored in patients with HIV infection.

Diminished androgen and estrogen receptors and aromatase levels in hypogonadal diabetic men: reversal with testosterone.

AIMS: One-third of males with type 2 diabetes (T2DM) have hypogonadism, characterized by low total and free testosterone concentrations. We hypothesized that this condition is associated with a compensatory increase in the expression of androgen receptors (AR) and that testosterone replacement reverses these changes. We also measured estrogen receptor and aromatase expression. MATERIALS AND METHODS: This is a randomized double-blind placebo-controlled trial. Thirty-two hypogonadal and 32 eugonadal men with T2DM were recruited. Hypogonadal men were randomized to receive intramuscular testosterone or saline every 2 weeks for 22 weeks. We measured AR, ERα and aromatase expression in peripheral blood mononuclear cells (MNC), adipose tissue and skeletal muscle in hypogonadal and eugonadal males with T2DM at baseline and after 22 weeks of treatment in those with hypogonadism. RESULTS: The mRNA expression of AR, ERα (ESR1) and aromatase in adipose tissue from hypogonadal men was significantly lower as compared to eugonadal men, and it increased significantly to levels comparable to those in eugonadal patients with T2DM following testosterone treatment. AR mRNA expression was also significantly lower in MNC from hypogonadal patients compared to eugonadal T2DM patients. Testosterone administration in hypogonadal patients also restored AR mRNA and nuclear extract protein levels from MNC to that in eugonadal patients. In the skeletal muscle, AR mRNA and protein expression are lower in men with hypogonadism. Testosterone treatment restored AR expression levels to that comparable to levels in eugonadal men. CONCLUSIONS: We conclude that, contrary to our hypothesis, the expression of AR, ERα and aromatase is significantly diminished in hypogonadal men as compared to eugonadal men with type 2 diabetes. Following testosterone replacement, there is a reversal of these deficits.