Beta-cell function in type 2 diabetes (T2DM): Can it be preserved or enhanced?

Type 2 diabetes (T2DM) is a complex metabolic disorder manifested by hyperglycemia, insulin resistance, and deteriorating beta-cell function. A way to prevent progression of the disease might be to enhance beta-cell function and insulin secretion. However, most previous studies examined beta-cell function while patients were using glycemia-lowering agents without an adequate period off medications (washout). In the present review we focus on studies with a washout period. We performed a literature search (2010 to June 2021) using beta-cell function and enhancement. The evidence shows that beta-cell function can be enhanced. Bariatric surgery and very low calorie diets show improvement in beta-cell function in many individuals. In addition, use of glucagon-like peptide-1 receptor agonists for prolonged periods (3 years or more) can also lead to improvement of beta-cell function. Further research is needed to understand the mechanisms leading to improved beta-cell function and identify agents that could enhance beta-cell function in patients with T2DM.

Primary Hyperaldosteronism: Approach to Diagnosis and Management.

Hyperaldosteronism is a relatively more common disorder than previously recognized. Patients with hyperaldosteronism are at high risk for cardiovascular events. Patients suspected of having hyperaldosteronism should undergo initial screening and subsequent confirmatory testing to establish a biochemical diagnosis. Although adrenal computed tomography/magnetic resonance imaging scans often define a disease's subtype, adrenal vein sampling, in order to determine lateralization, may be necessary in some patients who are surgical candidates. Medical therapy using optimal doses of mineralocorticoid receptor antagonists can control symptoms and normalize plasma renin activity. The long-term outcome of patients treated with either surgical or optimal medical therapy appears similar.

Management of diabetes in elderly patients during the COVID-19 pandemic: current and future perspectives.

Introduction: The COVID-19 pandemic has affected the entire population with the most deleterious effects in elders. Elders, especially those with diabetes, are at the highest risk of COVID-19 related adverse outcomes and mortality. This is usually linked to the comorbidities that accumulate with age, diabetes-related chronic inflammation, and the pandemic's psychosocial effects.Areas covered: We present some approaches to manage these complicated elderly patients with diabetes during the COVID-19 pandemic. In the inpatient setting, we suggest similar (pre-pandemic) glycemic targets and emphasize the importance of using IV insulin and possible use of continuous glucose monitoring to reduce exposure and PPE utilization. Outside the hospital, we recommend optimal glycemic control within the limits imposed by considerations of safety. We also describe the advantages and challenges of using various technological platforms in clinical care.Expert opinion: The COVID-19 pandemic has lifted the veil off serious deficiencies in the infrastructures for care at both the individual level and the population level and also highlighted some of the strengths, all of which affect individuals with diabetes and COVID-19. We anticipate that things will not return to 'normal' after the COVID-19 pandemic has run its course, but rather they will be superseded by 'New Normal.'

Factors leading to high morbidity and mortality of COVID-19 in patients with type 2 diabetes.

Coronavirus disease 2019 (COVID-19) is a recent pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus. Diabetes (mostly type 2 diabetes mellitus, T2DM) and hyperglycemia are among the major comorbidities in patients with COVID-19 leading to poor outcomes. Reports show that patients with diabetes and COVID-19 are at an increased risk for developing severe complications including acute respiratory distress syndrome, multi-organ failure, and death. Here we explore potential mechanistic links that could explain the observed higher morbidity and mortality in this patient population. Patients with T2DM have an underlying increased level of inflammation associated with obesity and insulin resistance in addition to other comorbidities including hypertension, obesity, cardiovascular disease, dyslipidemia, and being older. We review evidence that T2DM with hyperglycemia are among factors that lead to elevated expression of angiotensin-converting enzyme 2 (ACE2) in lungs and other tissues; ACE2 is the cellular "receptor" and port of viral entry. The preexisting chronic inflammation with augmented inflammatory response to the infection and the increasing viral load leads to extreme systemic immune response ("cytokine storm") that is strongly associated with increased severity of COVID-19. Based on the available evidence, it is recommended by a panel of experts that safe but stringent control of blood glucose, blood pressure, and lipids be carried out in patients with T2DM, measures that could potentially serve to decrease the severity of COVID-19 should these patients contract the viral infection. Once the infection occurs, then attention should be directed to proper glycemic control with use of insulin and frequent monitoring of blood glucose levels.

Glucocorticoid-Induced Fatty Liver Disease.

Glucocorticoids (GCs) are commonly used at high doses and for prolonged periods (weeks to months) in the treatment of a variety of diseases. Among the many side effects are increased insulin resistance with disturbances in glucose/insulin homeostasis and increased deposition of lipids (mostly triglycerides) in the liver. Here, we review the metabolic pathways of lipid deposition and removal from the liver that become altered by excess glucocorticoids. Pathways of lipid deposition stimulated by excess glucocorticoids include 1) increase in appetite and high caloric intake; 2) increased blood glucose levels due to GC-induced stimulation of gluconeogenesis; 3) stimulation of de novo lipogenesis that is augmented by the high glucose and insulin levels and by GC itself; and 4) increased release of free fatty acids from adipose stores and stimulation of their uptake by the liver. Pathways that decrease hepatic lipids affected by glucocorticoids include a modest stimulation of very-low-density lipoprotein synthesis and secretion into the circulation and inhibition of ß-oxidation of fatty acids. Role of 11ß-hydroxysteroid dehydrogenases-1 and -2 and the reversible conversion of cortisol to cortisone on intracellular levels of cortisol is examined. In addition, GC control of osteocalcin expression and the effect of this bone-derived hormone in increasing insulin sensitivity are discussed. Finally, research focused on gaining a better understanding of the dose and duration of treatment with glucocorticoids, which leads to increased triglyceride deposition in the liver, and the reversibility of the condition is highlighted.

Intermittent fasting and 'metabolic switch': Effects on metabolic syndrome, prediabetes and type 2 diabetes.

Various intermittent fasting (IF) dietary plans have gained popularity among obese individuals in recent years as a means of achieving weight loss. However, studies evaluating the effect of IF regimens in people with metabolic syndrome, prediabetes and type 2 diabetes (T2D) are limited. The aim of the present review was to briefly elucidate the biochemical and physiological mechanisms underlying the positive effects of IF, especially the effect of the proposed 'metabolic switch' on metabolism. Next, we examined the efficacy and safety of IF regimens in individuals with metabolic syndrome, prediabetes and T2D. To achieve this, we performed a MEDLINE PubMed search using combinations of various IF terms, including trials in which participants met the additional criteria for metabolic syndrome, prediabetes or T2D. We found four studies in individuals with metabolic syndrome, one study in people with prediabetes, and eight studies in people with T2D evaluating the effects of different IF regimens. The limited available evidence, with small sample sizes and short trial durations, suggests that IF regimens have a similar effectiveness compared with calorie-restriction diets for weight loss and improvement in glycaemic variables. In general, most IF regimens are effective and safe. However, there is an increased risk of hypoglycaemia in patients with T2D who are treated with insulin or sulphonylureas. Moreover, long-term adherence to these regimens appears uncertain. There is a need for large controlled randomized trials to evaluate the efficacy of IF regimens, especially in individuals with metabolic syndrome and prediabetes. If proven to be sustainable and efficacious for prolonged periods, IF could offer a promising approach to improving health at the population level, and would result in multiple public health benefits.

HYPOKALEMIC PERIODIC PARALYSIS IN A PATIENT WITH EUTHYROID GRAVES DISEASE AND CELIAC DISEASE.

OBJECTIVE: Thyrotoxic periodic paralysis is a sporadic form of hypokalemic periodic paralysis (HPP) that is most commonly seen in patients with Graves disease (GD) in association with acute thyrotoxicosis. A very few cases of HPP have been reported in patients with GD while the patient was euthyroid. METHODS: We describe a case of a 62-year-old Caucasian male with a history of GD, who presented with acute progressive bilateral lower extremity weakness. RESULTS: The patient was found to have severe hypokalemia, with no evidence of diarrhea or increased urinary potassium excretion. He was diagnosed as having HPP. He remained clinically and biochemically euthyroid during the admission. There was no history of high-carbohydrate meal intake, intense exercise, recent steroid exposure, or unusual stress. His symptoms improved gradually over the next 3 to 4 days with potassium supplementation. Nine months later, he progressed to overt hyperthyroidism and was treated with 25 mCi of iodine-131 and following that he has been on levothyroxine replacement for post-ablative hypothyroidism. Other unusual features in this patient were hypocalcemia, hypomagnesemia, and vitamin D deficiency during the acute presentation. Serum calcium and magnesium normalized 2 days after admission, while serum vitamin D continued to be low. He was later diagnosed to have celiac disease. CONCLUSION: Our case adds a rare presentation of HPP in a euthyroid patient with a known history of GD with associated celiac disease, hypomagnesemia, and hypocalcemia to the literature.

The Value of Perioperative Levels of ACTH, DHEA, and DHEA-S and Tumor Size in Predicting Recurrence of Cushing Disease.

Context and Objectives: Despite the development of hypocortisolemia after corticotroph surgical adenomectomy, 15% to 20% patients have recurrence of Cushing disease (CD). In this study, we investigated the effect of tumor size and the value of perioperative assessment of corticotropin (ACTH) and adrenal steroid levels in predicting recurrence. Design: Perioperatively, no glucocorticoids were administered until the serum cortisol was ≤3 µg/dL. Blood samples were obtained before and repeatedly after adenomectomy in 79 patients with CD. Of these, 66 had a nadir serum cortisol of ≤3.0 µg/dL and clinical and biochemical remissions. During a median follow-up of 131 months, 11 of 66 had disease recurrence (REC), whereas 55 of 66 did not (NO-REC). Results: Preoperative hormone levels in the REC and NO-REC groups were similar. After adenomectomy, a brief and similar increase in ACTH, cortisol, and dehydroepiandrosterone (DHEA) levels was observed in both groups followed by gradual decline in those levels. Although REC and NO-REC patients had similar cortisol levels (3.4 ± 1.7 µg/dL vs 2.9 ± 2.2 µg/dL) at the 36th postoperative hour, their respective ACTH (33 ± 7.1 ng/L vs 12.1 ± 5.4 ng/L; P < 0.0001), DHEA (3.8 ± 1.7 ng/mL vs 1.2 ± 1.1 ng/mL; P = 0.005), and dehydroepiandrosterone sulphate (DHEA-S) (143.9 ± 45.2 µg/dL vs 48.9 ± 38.2 µg/dL; P < 0.0001) were higher. At nadir hypocortisolemia, perioperative ACTH levels were >20 in all REC patients and <20 ng/L in the NO-REC group. Patients with REC had larger tumors than those with NO-REC. Conclusion: Recurrent CD is characterized by persistent perioperative ACTH secretion after adenomectomy. Higher perioperative levels of ACTH, DHEA, and DHEA-S are highly predictive of future disease recurrence, particularly in those with profound hypocortisolemia.

Clopidogrel-Induced Insulin Autoimmune Syndrome: A Newly Recognized Cause of Hypoglycemia in a Patient Without Diabetes.

Insulin autoimmune syndrome (IAS), defined as hyperinsulinemic hypoglycemia with high titers of anti-insulin antibodies, is frequently reported in Japanese patients but rarely observed in whites. We report in this study on a 79-year-old white male without diabetes who developed IAS following exposure to clopidogrel, a drug not previously known to cause hypoglycemia. The patient presented with recurrent symptomatic hypoglycemia. During one episode, serum glucose was 45 mg/dL, whereas insulin and C-peptide levels were 40,000 mIU/mL and 40 ng/mL, respectively. Additional studies revealed no intake of insulin or its secretagogues, whereas anti-insulin antibody titer was high (59.3 nmol/L). Although total insulin levels were consistently high, free insulin concentrations (polyethylene glycol precipitation) were appropriate for ambient glycemia. The patient was found to have HLA-DRB1*0404, a feature often reported in Japanese patients with IAS. Three weeks prior to symptom onset, he was started on clopidogrel, a drug that does not have a sulfhydryl group, but its active metabolite does. Clopidogrel was switched to a nonsulfhydryl antiplatelet agent, and glucocorticoid therapy was initiated. Shortly thereafter, the frequency of hypoglycemic episodes decreased, and glucocorticoids were tapered over the ensuing 3 months. No hypoglycemic episodes were noted during 6 months of observation after discontinuing glucocorticoids, whereas the total insulin and anti-insulin antibody levels normalized. The data indicate that IAS should be considered in the differential diagnosis of hyperinsulinemic hypoglycemia in seemingly well individuals, even when no drugs known to cause IAS were used. Clinical suspicion of IAS can avoid expensive imaging and unnecessary surgery in affected patients.

The impact of peri-operative dexamethasone administration on the normal hypothalamic pituitary adrenal response to major surgical procedures.

BACKGROUND: Surgical procedures are associated with activation of the hypothalamic-pituitary-adrenal axis (HPA). Studies examining HPA dynamics peri-operatively are limited and the modulating influence of peri-operatively administered glucocorticoids on that is not well established. This investigation examined alterations in HPA function and the impact of dexamethasone (DEX) administration during the peri-operative period. METHODS: We examined HPA function in 297 patients with normal function who had surgical procedures including pituitary mass resection (n = 191), craniotomy (n = 17) and other thoracic/ abdominal/ pelvic surgeries (n = 89). HPA function was assessed by frequent measurements of parameters defining adrenal function: ACTH, cortisol, DHEA and DHEA-S levels for 48 h. DEX was administered as a single dose (2-10 mg) to 30 and as multiple doses (12-36 mg) to 21 patients. The data of DEX-treated subjects within each group were similar and were combined together. RESULTS: Pre-operative data were similar for patients having different surgical procedures. Without DEX exposure, ACTH increased to 225 ± 100 ng/L at 2-4 h and gradually declined to baseline values by 36 h while cortisol levels peaked (39.2 ± 13.2 ug/dL) at 6-8 h declining gradually thereafter. Cortisol rise was paralleled by an equimolar increase in DHEA and a subsequent increase in DHEA-S levels. Single doses of DEX did not influence ACTH or cortisol secretion but suppressed the expected rise in DHEA and DHEA-S levels. Multiple doses of DEX suppressed ACTH and cortisol after the 15th postoperative hour and completely blocked the expected rise in DHEA and DHEA-S levels. CONCLUSIONS: The data provide a detailed overview of HPA function in a large number of subjects who had major surgical procedures. Single and large doses of DEX did not suppress ACTH or cortisol secretion but suppressed adrenal androgen secretion. It took multiple doses of DEX to partially suppress ACTH and cortisol secretion in the peri-operative period.

Perioperative hypothalamic pituitary adrenal function in patients with silent corticotroph adenomas.

BACKGROUND: Silent corticotroph adenomas (SCAs) are characterized by strong ACTH immunostaining without clinical manifestations of hypercortisolism. Patients with SCAs often present with mechanical symptoms related to tumor growth. This study investigates the hypothalamic pituitary adrenal axis (HPA) characteristics after adenomectomy in patients with SCAs. METHODS: Biochemical parameters of HPA function were monitored frequently after surgical resection of non-functioning macroadenomas. Levels of ACTH, cortisol, DHEA and DHEA-S were measured frequently for 48 h after adenomectomy. HPA data of patients with SCAs (n = 38) were compared to others (Controls) with non-secreting, ACTH-negative immunostaining adenomas of similar age and gender distribution (n = 182) who had adenomectomy. RESULT: Plasma ACTH increased (P < 0.0001) equally in patients with SCA and controls reaching a peak at 3 h (238 ± 123 vs. 233 ± 96 ng/L, respectively) after extubation declining thereafter to baseline values 24-36 h. Similarly, serum cortisol levels increased (P < 0.0001) equally in both groups reaching a maximum at 7 h (36.8 ± 13.9 vs. 39.3 ± 13.3 ug/dL). Serum DHEA also increased (P < 0.001) equally in both groups in parallel to the rise in serum cortisol. Serum DHEA-S levels similarly increased (P < 0.001) from their respective baseline (105.9 ± 67.5 and 106.5 ± 58.7 ug/dL) reaching their peak (154.5 ± 69.5 and 153.5 ± 68.6 ug/dL; respectively) at 15 h after extubation. None of the patients acquired any hormone deficits. CONCLUSIONS: Under the maximal stimulation of the peri-operative stress, HPA function in patients with SCA behaved in an identical manner to others with ACTH-negative macroadenomas. Thus, despite the strong ACTH-positive immunostaining of these tumors, SCAs are truly non- functional.

Effects of transaldolase exchange on estimates of gluconeogenesis in type 2 diabetes.

Transaldolase (TA) exchange overestimates gluconeogenesis measured with deuterated water (²H2O). However, it is unknown whether TA differs in people with type 2 diabetes (T2DM). ²H2O was ingested, and [1-¹³C]acetate and [3-³H]glucose were infused in T2DM (n = 10) and healthy nondiabetic (ND; n = 8) subjects. TA was assessed from the ratio of ¹³C3 to ¹³C4 glucose enrichment (¹³C3/¹³C4) measured by ¹³C NMR. Glucose turnover was measured before (~16-h fast) and during hyperglycemic (~10 mM) moderate-dose insulin (~0.35 mU·kg⁻¹·min⁻¹) clamp. ¹³C3/¹³C4 in T2DM vs. ND was <1.0 and not different at baseline and clamp, indicating equivalent TA. To determine whether incomplete triose phosphate isomerase (TPI) exchange contributed to asymmetric ¹³C3/¹³C4, [U-¹³C]glycerol was infused in lieu of [1-¹³C]acetate during a separate visit in a subset of ND (n = 7) subjects. Ratio of ¹³C3/¹³C4 obtained following either tracer was <1.0 at baseline and during clamp, indicating that TPI exchange was essentially complete and did not contribute to asymmetric glucose enrichment. Uncorrected and corrected rates of gluconeogenesis were no different (P = not significant) in T2DM vs. ND both at baseline and during clamp. TA correction resulted in equivalent estimates of corrected gluconeogenesis in T2DM and ND that were ~25-35% lower than uncorrected gluconeogenesis both at baseline and during the clamp. The asymmetric enrichment of glucose from ¹³C-gluconeogenic tracers is attributable to TA exchange and can be utilized to correct for TA exchange. In conclusion, TA exchange does not differ between T2DM and ND under fasting or hyperglycemic clamp conditions, and the ²H2O method continues to provide an accurate estimation of gluconeogenesis.

Experiences with a novel policy for managing conflicts of interest of guideline developers: a descriptive qualitative study.

BACKGROUND: The executive committee of the Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (AT9) developed a novel policy for managing conflicts of interest (COIs): Methodologists bore primary responsibility for each chapter, there was equal emphasis on intellectual and financial COI, and content experts with COIs participated, but with restrictions for recommendations on which they had conflicts. The objective of this study was to explore the experiences of the methodologists and content experts with the COI policy after its implementation. METHODS: One investigator conducted two rounds of semistructured interviews with the methodologist and the leading content expert of each chapter until data saturation was achieved. Two investigators analyzed the transcripts of the interviews in duplicate using an immersion-crystallization approach. We also conducted member checking. RESULTS: We interviewed 15 participants and presented the results to the remaining four for verification. In comparison with their views expressed prior to AT9 development, methodologists remained more positive about the policy than content experts. Six of 10 content experts expressed a more positive view than prior to participation in the AT9 process. The other four content experts remained skeptical, especially regarding the emphasis on intellectual COI. The restrictions of the policy on conflicted individuals were not fully implemented. CONCLUSIONS: After its implementation, some content experts were more favorable to the policy, but some retained major reservations. The influence of the policy on recommendations may have been more through the leading role of the methodologists than exclusion of conflicted participants in making recommendations.