Sleep Apnea, Obesity, and Diabetes - an Intertwined Trio.

PURPOSE OF REVIEW: To synthesize the existing literature regarding the complex interplay between sleep disturbance, obesity, and diabetes. The review emphasizes the three pillars of health being diet, exercise, and sleep, with the notion that if one is ignored, then the other two could suffer. RECENT FINDINGS: Sleep deprivation is associated with incident obesity, perhaps mediated by dysregulation in leptin and ghrelin - hormones important in regulation of appetite. Sleep apnea is very common particularly among obese people with type 2 diabetes mellitus. Treatment of sleep apnea has clear symptomatic benefits although its impact on long-term cardiometabolic health is less clear. Sleep disturbance may be an important modifiable risk for patients at risk of cardiometabolic disease. An assessment of sleep health may be an important component of the comprehensive care of patients with obesity and diabetes mellitus.

Metformin Use in Diabetes Prior to Hospitalization: Effects on Mortality in Covid-19.

OBJECTIVE: Although type 2 diabetes mellitus (T2DM) has been reported as a risk factor for coronavirus disease 2019 (COVID-19), the effect of pharmacologic agents used to treat T2DM, such as metformin, on COVID-19 outcomes remains unclear. Metformin increases the expression of angiotensin converting enzyme 2, a known receptor for severe acute respiratory syndrome coronavirus 2. Data from people with T2DM hospitalized for COVID-19 were used to test the hypothesis that metformin use is associated with improved survival in this population. METHODS: Retrospective analyses were performed on de-identified clinical data from a major hospital in Wuhan, China, that included patients with T2DM hospitalized for COVID-19 during the recent epidemic. One hundred and thirty-one patients diagnosed with COVID-19 and T2DM were used in this study. The primary outcome was mortality. Demographic, clinical characteristics, laboratory data, diabetes medications, and respiratory therapy data were also included in the analysis. RESULTS: Of these 131 patients, 37 used metformin with or without other antidiabetes medications. Among the 37 metformin-taking patients, 35 (94.6%) survived and 2 (5.4%) did not survive. The mortality rates in the metformin-taking group versus the non-metformin group were 5.4% (2/37) versus 22.3% (21/94). Using multivariate analysis, metformin was found to be an independent predictor of survival in this cohort (P = .02). CONCLUSION: This study reveals a significant association between metformin use and survival in people with T2DM diagnosed with COVID-19. These clinical data are consistent with potential benefits of the use of metformin for COVID-19 patients with T2DM.

Hyperthyroidism Due to Graves Disease After Radiofrequency Ablation.

Management options for benign, autonomously functioning, and malignant thyroid nodules were limited to surgery or targeting by radioactive iodine before the availability of radiofrequency ablation (RFA). Despite being a relatively new technique, RFA may be favored for patients of high surgical risk, and for those who wish to avoid hypothyroidism. Although insurance coverage for the procedure can be a significant barrier, several groups of investigators have shown improved quality of life for RFA compared to surgery, due to the less invasive nature and favorable risk profile. Hyperthyroidism due to transient thyroiditis is a known risk of RFA, secondary to direct trauma and subsequent thyroid hormone release. Here we present a case of an adult with large, symptomatic, multinodular goiter, with no prior history of thyroid autoimmunity, who underwent RFA with successful volume reduction of two nodules, but who developed acute hyperthyroidism due to Graves disease eight weeks after RFA. Larger studies evaluating the risks of RFA should evaluate for incident hyperthyroidism, specifically for Graves disease/thyroid autoimmunity, as this could represent an additional risk of the procedure.

Inpatient use of metformin and acarbose is associated with reduced mortality of COVID-19 patients with type 2 diabetes mellitus.

AIMS: Type 2 diabetes mellitus (T2DM) is a strong risk factor for complications of coronavirus disease 2019 (COVID-19). The effect of T2DM medications on COVID-19 outcomes remains unclear. In a retrospective analysis of a cohort of 131 patients with T2DM hospitalized for COVID-19 in Wuhan, we have previously found that metformin use prior to hospitalization is associated with reduced mortality. The current study aims to investigate the effects of inpatient use of T2DM medications, including metformin, acarbose, insulin and sulfonylureas, on the mortality of COVID-19 patients with T2DM during hospitalization. METHODS: We continue to carry out a retrospective analysis of a cohort of 131 patients with T2DM hospitalized for COVID-19 and treated with different combinations of diabetes medications. RESULTS: We found that patients using metformin (p = .02) and acarbose (p = .04), alone or both together (p = .03), after admission were significantly more likely to survive than those who did not use either metformin or acarbose. 37 patients continued to take metformin after admission and 35 (94.6%) survived. Among the 57 patients who used acarbose after admission, 52 survived (91.2%). A total of 20 patients used both metformin and acarbose, while 57 used neither. Of the 20 dual-use patients, 19 (95.0%) survived. CONCLUSION: Our analyses suggest that inpatient use of metformin and acarbose together or alone during hospitalization should be studied in randomized trials.

Fasting hypoglycaemia secondary to carnitine deficiency: a late consequence of gastric bypass.

Twelve years following gastric bypass surgery, a cachectic 69-year-old woman presented with both fasting and postprandial hypoglycaemia. Postprandial symptoms were relieved by dietary modification and acarbose, as is common in such cases. During a supervised fast, symptomatic hypoglycaemia occurred. Concurrent laboratory testing showed suppression of plasma insulin, c-peptide, proinsulin and insulin-like growth factor II. However, beta-hydroxybutyrate was also low, surprising given insulin deficiency. Elevated plasma free fatty acid (FFA) concentrations suggested that lipolysis was not impaired, making cachexia/malnutrition a less likely cause of hypoglycaemia. The apparent diagnosis was failure to counter-regulate-subsequent plasma carnitine measurements showed carnitine deficiency which presumably prevented FFA transport across mitochondrial membranes for ketogenesis. Repletion with high-dose oral carnitine supplements effected resolution of fasting hypoglycaemia.

Inappropriate requesting of parathyroid scintigraphy at an academic medical center.

BACKGROUND: Primary hyperparathyroidism is a biochemical, not radiologic diagnosis. Parathyroid scintigraphy should only be requested for surgical planning, not to confirm diagnosis. Here we determined reasons for inappropriately ordered parathyroid scintigraphy. METHODS: We generated a database of patients undergoing parathyroid scintigraphy over 5 years, who did not undergo parathyroidectomy. RESULTS: Over 5 years 129 parathyroid scintigraphies (of 308 total scans) were performed in patients who did not undergo parathyroidectomy. We determined that only 58 (45%) had true primary hyperparathyroidism. The most common reason for the scan was to "confirm the diagnosis." Only 20% were ordered for adenoma localization, although surgery was not performed. Physicians requesting parathyroid scintigraphies specialized in a variety of disciplines. CONCLUSION: Forty-two percent of parathyroid scintigraphies were requested inappropriately to "confirm" a diagnosis of primary hyperparathyroidism. We propose to change the ordering system to clarify that parathyroid scintigraphy is a functional tool to optimize surgery when the diagnosis is secure.

ACE2, Metformin, and COVID-19.

COVID-19 is becoming a leading cause of mortality throughout the world, and few effective therapies are currently available. Angiotensin converting enzyme 2 (ACE2) is essential to COVID-19 pathogenesis, as the binding of SARS-CoV-2 spike protein (S protein) is required for viral entry and development of COVID-19. ACE2 regulates the protective arm of the renin-angiotensin-aldosterone system (RAAS) that endows anti-hypertensive and anti-inflammatory effects in the cardiovascular and pulmonary systems. Preclinical data suggest ACE2 might be downregulated after SARS-CoV-2 binding, and treatments that increase ACE2 may prevent cardiopulmonary injury. Development, testing, and mass production of novel ACE2 therapies may take years, whereas more effective treatments for COVID-19 are needed urgently. Metformin is a widely available anti-diabetic agent that has an excellent safety profile, and clinical and preclinical data suggest metformin may offer cardiopulmonary protection in COVID-19 via enhanced ACE2 expression.

Rebound Vertebral Fractures in a Patient With Lung Cancer After Oncology-Dose Denosumab Discontinuation: A Cautionary Tale.

We describe a 55-year-old woman with lung cancer complicated by bone metastases. Treatment with denosumab (120 mg monthly) was interrupted after 9 doses because of concern for potential osteonecrosis of the jaw during upcoming dental work. Fifteen months after receiving the last dose of denosumab, the patient presented with 7 atraumatic spinal compression fractures requiring kyphoplasty for symptom relief. No malignancy was found in pathology specimens. Evaluation for secondary causes of osteoporosis was negative. This phenomenon of rebound fractures after discontinuing the use of denosumab, an inhibitor of RANK ligand, has been well described in patients with osteoporosis, who receive much lower doses than do patients with cancer. However, this has not been previously reported in oncology patients, likely because most succumb to their disease before denosumab therapy is stopped.

Liver and skeletal muscle lipids have differing fatty acid profiles in short-gut rats fed via parenteral nutrition.

BACKGROUND: In short-gut rats, we showed marked abnormalities in plasma lipid fatty acids using parenteral nutrition (PN) with lipid vs sham surgery rats. This suggests that either sensing or metabolism of parenteral lipid is abnormal in malabsorption. The goal of this study was to determine fatty acid profiles in skeletal muscle and liver in short-gut rats treated with PN compared with sham rats. METHODS: Sprague-Dawley rats underwent laparotomy and massive small bowel resection (or sham surgery). Rats (n = 32, 16 sham, 16 short gut) were randomly assigned to PN with lipid or fat-free PN. After 5 days, weight loss was similar in all groups, and mixed hindlimb skeletal muscle and liver were biopsied. RESULTS: We found marked differences between liver and skeletal muscle. In livers of short-gut animals, 22:4omega6, 22:5omega6, and 22:6omega3 were higher (all p < .05) than in sham. In skeletal muscle, short gut had no effect on fatty acid profiles. In liver, fat-free PN led to significant increases in 20:3omega6, 22:4omega6, 22:5omega6, 20:3omega9, 20:5omega3, 22:6omega3, and triene/tetraene ratio (all p < .05) compared with feeding PN with lipid, irrespective of short gut. In muscle, levels of the distal long-chain fatty acid metabolites and triene/tetraene ratio were minimally affected by nutrition. Serum glucose and insulin concentrations were similar in all 4 groups. CONCLUSIONS: Both the presence of short gut and type of PN led to increases in distal metabolites of fatty acids on omega:3 and omega:6 pathway in liver phospholipids but not in skeletal muscle during short-term PN feeding in rats.

Immunonutrition: problematic or problem solving?

The addition of immune-modulating nutrients to enteral formulas has been examined in clinical trials and meta-analyses. Enhancing immunity through diet is generally done by adding n-3 fatty acids, arginine, and nucleotides to an otherwise nutritionally complete formula. Despite flaws in many studies, a consistent trend to reduced infectious complications has been seen with immunonutrition, especially in patients undergoing surgery for upper gastrointestinal cancer or trauma. In critical care populations, however, the results have been mixed. In this review, we analyze these studies and focus on select clinical points that may explain the variation. One common flaw has been a failure to deliver an adequate nutrition volume. Few patients, especially in the earliest studies, received even close to goal feeding. A minimum quantity of immunonutrition may be required for effective reduction in infections. When feeding volumes are low, immunonutrition is usually not better than an isonitrogenous control. In more recent studies, practitioners have been increasingly aggressive with enteral feeding, and this has been reflected in improved outcomes from immunonutrition. Early delivery of immunonutrition (preoperatively in surgical patients with cancer) might be particularly beneficial. Another consideration is illness severity: we discuss evidence that the use of immunonutrition in moderate illness is more likely to be helpful, whereas severe sepsis is probably beyond the reach of any nutritional intervention, and mild illness is more likely to improve irrespective of feeding. If future trials can consider these vital points, level 1 recommendations in favor of immunonutrition might be justified, although presently such evidence is lacking for most clinical indications.

Patterns of plasma leptin and insulin concentrations in hospitalized patients after the initiation of total parenteral nutrition.

BACKGROUND: The regulation of leptin in patients with critical illness is poorly understood. Sex, diet, body mass, and cytokines may all play a role. OBJECTIVE: The aims of this study were to determine the factors influencing leptin concentrations in hospitalized patients beginning total parenteral nutrition (TPN) and whether a 3-d regimen of TPN would further increase plasma leptin concentrations above baseline. DESIGN: Twenty-six patients requiring TPN were enrolled in this prospective, nonintervention study. Only 20 (11 women and 9 men) completed all 3 d of TPN. RESULTS: Baseline plasma leptin in the TPN patients ranged from 62.5 to 1625 pmol/L ( +/- SD: 419 +/- 387; n = 26) and was not significantly different between men (444 +/- 494 pmol/L) and women (363 +/- 244 pmol/L). Baseline plasma insulin ranged from 76 to 695 pmol/L (271 +/- 188; n = 26) and was not correlated with plasma leptin. Leptin concentrations increased after 3 d of TPN, from 356 +/- 300 to 794 +/- 600 pmol/L (P < 0.05) in parallel with an increase in insulin from 257 +/- 187 to 979 +/- 917 pmol/L (P < 0.01) in the 20 patients who completed the study; however, the changes were not correlated when expressed as percentages. Although the men and women had insulin responses to feeding that were not significantly different, leptin concentrations did not increase significantly in men but increased 3-fold in women (to 1094 +/- 638 pmol/L; P < 0.01). CONCLUSIONS: Leptin regulation in patients with a critical illness differs substantially from that in healthy persons. The importance of glucose and insulin in leptin secretion remains unclear, especially in men.

Abnormal regulation of serum lipid fatty acid profiles in short gut rats fed parenteral nutrition with lipid.

Despite absence of essential fatty acid deficiency (EFAD), increases in arachidonic acid to linoleic acid ratios occur in serum phospholipid of patients treated with chronic total parenteral nutrition (TPN). The parenteral lipid component of TPN contains abundant linoleate; thus low phospholipid linoleate may reflect increased conversion to arachidonate. Arachidonic acid excess has been associated with a proinflammatory milieu through increased eicosanoid production and might contribute to the increases in inflammatory markers seen in home TPN patients. We investigated fatty acid metabolism in a rodent model of malabsorption. We hypothesized that short gut rats would metabolize parenteral lipid differently from intact rats. We performed laparotomy and 80% small bowel resection (or sham surgery) in rats. Sixteen sham and 16 short gut rats were randomly assigned to TPN with lipid or fat-free TPN. After 5 days, weight loss was similar in all groups. Analysis of serum phospholipids demonstrated that 20:3omega9 (eicosatrienoic acid) was relatively increased in fat-free TPN groups, irrespective of surgery type, as were distal very long chain omega3 class fatty acids, as anticipated. Uniquely, both nutrition (TPN/lipid v fat-free TPN) and surgery type (sham v short gut) were significant in determining arachidonic acid levels. Relatively elevated arachidonate occurred in both groups of fat-free rats, suggesting increased Delta6 and/or Delta5 desaturase activity, as expected. In contrast, giving TPN/lipid lowered arachidonate (suggesting appropriately downregulated desaturases) in sham animals, but not in short gut animals. Ratios of arachidonic and di-homo-gamma-linolenic to linoleic acids further suggested increased turnover of precursor omega6 to arachidonic acid in short gut rats given lipid compared with the other groups. These preliminary data show that intravenous (IV) lipid gave rise to serum lipid fatty acid profiles that differed in short gut and sham rats. The short gut rat may have a heightened hepatic desaturase activity, inappropriate for the quantity of linoleic acid provided parenterally. Therefore, the short gut rat is an appropriate model to study further arachidonic acid excess in home TPN patients.

Hyperglycemia and nutrition support: theory and practice.

Hyperglycemia has long been known to portend a worse short-term prognosis than euglycemia in hospitalized patients. Hyperglycemia reflects illness severity and results in deleterious consequences for certain patient groups. In a surgical intensive care unit population, normalization of morning glucose values using insulin infusions improved mortality vs controls. Until additional studies in other patient groups are reported, practitioners of nutrition support must prevent excessive iatrogenic hyperglycemia, in particular when using parenteral feeding, and should choose aggressive glycemic goals that also avoid hypoglycemia.

A simple method of supplementation of omega-3 polyunsaturated fatty acids: use of fortified yogurt in healthy volunteers.

BACKGROUND: A relative dietary ω-3 fatty acid deficiency exists in Western diets, and this deficiency may be associated with some chronic diseases. The aim of the present study was to supplement yogurt with docosahexaenoic acid and assess whether this fatty acid could be incorporated into plasma lipids. METHODS: We developed a stable emulsion of docosahexaenoic acid that was incorporated into yogurt. Twelve healthy volunteers agreed to consume 1 serving daily that contained 600 mg of docosahexaenoic acid. RESULTS: After 3 weeks of supplementation, plasma phospholipid docosahexaenoic acid content increased significantly, by 32%, in parallel with a 16% rise in total ω-3 fatty acids. This result was associated with a significant 7% decline in phospholipid arachidonic acid. CONCLUSIONS: Fortification of ordinary foods with docosahexaenoic acid is a potentially attractive method of increasing ω-3 fatty acid content of plasma lipids, and might even lower arachidonic acid concentrations.

Effect of a fish oil-containing beverage on changes in plasma lipid fatty acids in patients with malabsorption.

BACKGROUND: The aim of this pilot study was to assess tolerance of a beverage containing ω-3 fatty acids (fish oil) in patients with malabsorption receiving chronic parenteral nutrition (PN). The authors wanted to determine whether fish oil could be absorbed and incorporated into plasma fatty acids and reduce markers of inflammation. METHODS: This was a small intervention study in home-dwelling PN-dependent patients with chronic malabsorption. Ten patients were provided a drink containing 1.5 g of fish oil per day for 12 weeks. Baseline and post-supplement serum fatty acid profiles were compared. RESULTS: Five of 10 patients withdrew from the study because of GI side effects, principally worsened diarrhea, associated with the supplement. Modest increases were found in 20:5ω-3, 22:5ω-3, and 22:6ω-3 levels in both phospholipids and triglycerides in plasma (all P < .05). In phospholipids, a reduced arachidonic acid level was seen (P = .02). These changes were not sufficient to effect improvements in serum tumor necrosis factor-alpha (TNFα), soluble TNF receptor, C-reactive protein, or interleukin-6. CONCLUSIONS: Some patients with severe malabsorption can absorb oral ω-3 fatty acid supplements and incorporate these fatty acids into serum phospholipids and triglycerides. However, side effects are very common, and no anti-inflammatory effect was found, presumably related to the modest level of fatty acid change.