High-dose Insulin Research Articles

Relation between Exogenous Insulin and Cognitive Function in Type 2 Diabetes Mellitus.

Background and objectives: Although the role of insulin in the periphery is well understood, not as much is known about its multifactorial role in the brain. The aim of this study is to determine whether exogenous insulin, evaluated by daily insulin requirement, has an impact on mild cognitive impairment (MCI), and whether this relationship is mediated by insulin doses and other risk factors. Materials and methods: A sample of 100 participants with type 2 diabetes aged 40 and over was divided into case and control groups, according to their insulin requirement. Patients with an insulin requirement >1 IU/kg/day were assessed as the case group whereas those with an insulin dose <1 IU/kg were used as the control group. All participants underwent cognitive testing using MoCA questionnaire scoring and blood analysis to determine lipid and uric acid levels in plasma. Subjects were categorized as having normal cognitive function or MCI. Results: Results showed that the prevalence of MCI in Lithuanian elderly diabetic patients was high in the groups with a normal insulin requirement or high insulin requirement at 84.8% and 72.5%, respectively (p = 0.14). Age (p = 0.001) and insulin dose (p < 0.0001) were related to the MCI. Using ROC curve analysis, the highest rate risk of MCI occurred when the insulin dose was lower than 144 IU/d. Conclusions: In summary, the results of this study provided evidence that increased exogenous insulin supply improves cognitive function. Higher insulin dose (>144 IU/d) demonstrated a positive effect on cognitive function, especially in individuals with poorly controlled diabetes (HbA1c ≥ 9%). Finally, the prevalence of MCI in the T2DM population was found to be very high. Future research is needed to determine whether high exogenous insulin doses have a protective effect on MCI.

Determination of insulin-related lipohypertrophy frequency and risk factors in patients with diabetes

IntroductionInsulin, which is used in the treatment of diabetes mellitus (DM), may lead to the development of lipohypertrophy (LH) which can negatively affect the management of diabetes mellitus. Two common methods to detect LH are palpation and superficial subcutaneous ultrasonography (SSU). We investigated the frequency of non-palpable LH using SSU, as well as examining risk factors. MethodWe included in our study patients who had been receiving insulin injections at least twice a day for over one year without palpable LH. The epidermis and the subcutaneous tissue thickness of each region were examined using SSU. The presence of LH and associated risk factors for LH were evaluated. ResultsWe included 136 patients in our study. The mean age of all patients was 52.87±14.93 years, 59.6% were female and 73.5% had type 2 DM. The duration of DM and insulin usage were 15.76±9.20 and 11.42±8.26 years, respectively. The mean body mass index (BMI) of all patients was 30.59±7.40kg/m2. Non-palpable LH was detected in 87.5% (n=116) of the patients using SSU. In the multivariate logistic regression analyses, total cholesterol level, short-acting insulin dose and coronary artery disease (CAD) were associated with LH presence. ConclusionNon-palpable LH can be seen at high rates in patients who have multiple insulin injections. Palpation is likely not enough to detect LH and we believe it would be appropriate to evaluate the presence of LH using SSU, especially for those who need high-dose insulin to control hyperglycaemia.

A Case Report: An Overweight Patient with High Dose Insulin Usage

Abstract: Insulin is vital for patients with type 1 diabetes and useful for certain patients with type 2 diabetes [1]. In this article we aim to explain a case wrongly using high dosage insulin. A 68-year-old female patient with known 10 years of type 2 diabetes mellitus and hypertension came to our outpatient clinic because her blood glucose levels were high at home. She was using perindopril 10 mg, metformin and insulin. Since the patient did not want to make multiple injections her previous doctor has changed her therapy from glargine u300 1x50 units and insulin aspart 3x30 units to a mixed insulin; insulin degludec + insulin aspart, as 2x 40 units per day. However, the patient did not understand the change of treatment and made the combination of insulin glargine u300 1x50 units and insulin degludec + insulin aspart two times a day as 30 units. She was using this therapy more than two months. Diabetes and complications of diabetes is a challenging healthcare problem. Especially patients’ education is as important as the drug therapy [2, 3]. Among serious side-effects of insulin therapy are overdose, resulting in severe hypoglycemia, causing seizures, coma and even death [1]. Patients must be well educated about the risks of using high doses of insulin. Keywords: High dose insulin, Obesity, Type 2 diabetes mellitus, Patient education, Hypoglycemia, Insulin overdose

Glucose control using an artificial pancreas in a severe COVID-19 patient on extracorporeal membrane oxygenation: a case report

The usefulness and safety of continuous glucose monitoring (CGM) systems in adult patients with severe coronavirus disease (COVID-19) have been reported. Using CGM might reduce the exposure patients and healthcare workers to COVID-19 and limit the use of personal protective equipment during the pandemic. CGM devices measure glucose in the subcutaneous interstitial fluid, but the accuracy of this technique has not been established in critically ill patients. The artificial pancreas, STG-55 (Nikkiso, Tokyo), is a closed-loop device that conducts continuous blood glucose monitoring using a peripheral vein. We used the STG-55 for glucose control in a 60-year-old woman with severe COVID-19 admitted to the intensive care unit. Due to severe respiratory failure, the patient was intubated, and extracorporeal membrane oxygenation was introduced. Because she had hyperglycemia despite high-dose intravenous insulin therapy, we decided to use STG-55 for glucose control. The STG-55 safely titrated the insulin infusion and monitored glucose levels. Fifty-six hours after adopting the STG-55, it was removed because the blood sampling failed. No episodes of hypoglycemia were observed despite deep sedation during this period. In conclusion, this case demonstrates the potential utility of an artificial pancreas in patients with severe COVID-19.

SARS-COV-2 infection outcomes in patients with congenital generalized lipodystrophy

BackgroundA new strain of human coronavirus (HCoV) spread rapidly around the world. Diabetes and obesity are associated with a worse prognosis in these patients. Congenital Generalized Lipodystrophy (CGL) patients generally have poorly controlled diabetes and require extremely high doses of insulin. There is no documentation in the literature of cases of COVID in CGL patients. Thus, we aimed to evaluate the prevalence of SARS-CoV-2 infection in CGL patients, and the association of their clinical and metabolic characteristics and outcomes.MethodsThis is a cross-sectional study carried out between July and October 2020. Clinical data collected were respiratory or other flu-like symptoms, need of hospitalization in the last three months, CGL comorbidities, and medications in use. Cholesterol, triglycerides, glycohemoglobin A1c levels, anti-SARS-CoV-2 antibodies and nasopharyngeal swab for RT-qPCR were also obtained in all CGL patients. Mann-Whitney U test was used to analyze the characteristics of the participants, verifying the non-adherence of the data to the Gaussian distribution. In investigating the association between categorical variables, we used Pearson's chi-square test and Fisher's exact test. A significance level of 5% was adopted.ResultsTwenty-two CGL patients were assessed. Eight subjects (36.4%) had reactive anti-SARS-CoV-2 antibodies. Only one of these, also presented detectable RT-qPCR. Five individuals (62.5%) were women, median age of 13.5 years (1 to 37). Symptoms like fever, malaise, nausea, diarrhea and chest pain were present, and all asymptomatic patients were children. All subjects had inadequate metabolic control, with no difference between groups. Among positive individuals there was no difference between those with AGPAT2 (75%) and BSCL2 gene mutations (25%) (p > 0.05). No patient needed hospitalization or died.ConclusionsWe described a high prevalence of SARS-CoV-2 infection in CGL patients with a good outcome in all of them. These findings suggest that at least young CGL patients infected by SARS-COV-2 are not at higher risk of poor outcome, despite known severe metabolic comorbidities.

141-LB: MOVE! Enhanced: A Virtual Diabetes and Weight Management Pilot

Obese Veterans with diabetes and other comorbidities are at increased risk for complications and mortality. In this pilot, we examined the effectiveness of a multidisciplinary virtual intervention aimed to achieve weight loss and improve glycemic control in 10 high-risk obese Veterans with diabetes. Inclusion criteria were: age 18-75, BMI ≥ 30, A1c ≥ 8% or on high insulin doses (≥ 1 unit/kg or any dose of U-500 insulin), and at least one of the following: cardiovascular, kidney, nonalcoholic fatty liver, degenerative joint disease, or sleep apnea. All patients were recruited by the MOVE! Coordinator and enrolled in the Home Telehealth Program for diabetes and weight management. Participants worked with the dietitian to restrict carbohydrate intake (goal of 30-45 grams/meal) and with the occupational therapist to increase their physical activity through virtual sessions. A clinical pharmacist reviewed medications and made therapeutic recommendations in collaboration with the diabetes physician. Weekly huddles were held where information including glucose trends were discussed for each patient. With a mean duration of 5.5 months, participants have shown on average significant weight loss (-21.5 lbs or - 8.3%), improvement in glycemic control (-1.1% A1c), and decreased total daily insulin doses (-52.6%). At the end of the 12 months pilot duration, changes in other cardiometabolic markers, impact on quality of life, and cost will be assessed.View largeDownload slideView largeDownload slide DisclosureC. E. Mendez: None. J. M. Hansen: None. A. Feest: None. J. Taxman: None. K. Bertram: None. A. V. Hanley: None.

Differential insulin sensitivity of NMR-based metabolomic measures in a two-step hyperinsulinemic euglycemic clamp study

BackgroundInsulin is the key regulator of glucose metabolism, but it is difficult to dissect direct insulin from glucose-induced effects. We aimed to investigate the effects of hyperinsulemia on metabolomic measures under euglycemic conditions in nondiabetic participants.MethodsWe assessed concentrations of 151 metabolomic measures throughout a two-step hyperinsulinemic euglycemic clamp procedure. We included 24 participants (50% women, mean age = 62 [s.d. = 4.2] years) and metabolomic measures were assessed under baseline, low-dose (10 mU/m2/min) and high-dose (40 mU/m2/min) insulin conditions. The effects of low- and high-dose insulin infusion on metabolomic measures were analyzed using linear mixed-effect models for repeated measures.ResultsAfter low-dose insulin infusion, 90 metabolomic measures changed in concentration (p < 1.34e−4), among which glycerol (beta [Confidence Interval] = − 1.41 [− 1.54, − 1.27] s.d., p = 1.28e−95) and three-hydroxybutyrate (− 1.22 [− 1.36, − 1.07] s.d., p = 1.44e−61) showed largest effect sizes. After high-dose insulin infusion, 121 metabolomic measures changed in concentration, among which branched-chain amino acids showed the largest additional decrease compared with low-dose insulin infusion (e.g., Leucine, − 1.78 [− 1.88, − 1.69] s.d., P = 2.7e−295). More specifically, after low- and high-dose insulin infusion, the distribution of the lipoproteins shifted towards more LDL-sized particles with decreased mean diameters.ConclusionMetabolomic measures are differentially insulin sensitive and may thus be differentially affected by the development of insulin resistance. Moreover, our data suggests insulin directly affects metabolomic measures previously associated with increased cardiovascular disease risk.

921-P: Do Glucose and Lipid Metabolism Differ by Adiposity in Adolescents with Type 1 Diabetes (T1D)? Preliminary Results of a 2-Step Clamp Study

Puberty is a known stage of insulin resistance in lean adolescents with or without T1D. Moreover, 25% of adolescents with T1D in clinical practice are overweight, which may further contribute to insulin resistance. The present study examines whether higher body fat aggravates insulin resistance in the liver, muscle, and adipose tissue in pubertal adolescents with T1D by performing a 2-step, 8 and 80 mU/m2/min hyperinsulinemic euglycemic clamp. Body Composition was measured by DEXA, abdominal fat by MRI and hepatic fat by MRI-proton density fat fraction (PDFF). Endogenous glucose production and glycerol turnover were traced with [6,6-2H2] glucose and [2H5]-glycerol (Figure). Participants (mean age 14.4±1.2 years, A1c 7.6±0.5%) with lower (22.9) and higher (36.7) mean % body fat had mean weights of 61.6 and 68.1 kg, BMI% 68.3 and 84.8, and PDFF 1.4 and 1.7%, respectively. Endogenous glucose production was partially suppressed across the body fat spectrum during the low dose insulin infusion. In contrast, those with higher body fat tended to have diminished suppression of glucose production during the high dose insulin infusion. Rates of lipolysis appear to be unaffected. Hence our preliminary findings suggest that on the spectrum of increasing body fat in pubertal adolescents with T1D, we start to see metabolic inflexibility in youth with a moderate degree of adiposity. Disclosure M. A. Van name: None. S. Siebel: None. E. M. Tichy: None. S. Caprio: None. W. V. Tamborlane: Consultant; Self; Medtronic, Sanofi, Other Relationship; Self; Tolerion, Inc. N. Santoro: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (1K23DK115894-01A1)

Abstract #976395: Case Series: COVID-19 Infection Causing New-Onset Diabetes Mellitus?

There is a bidirectional relationship between COVID-19 and diabetes. Not only diabetes is associated with an increased risk of severe COVID-19 but also new-onset diabetes and severe metabolic complications of preexisting diabetes, including diabetic ketoacidosis and hyperosmolarity for which exceptionally high doses of insulin are warranted, have been observed in patients with Covid-19. This paper seeks to explore the hypothesis of the potential diabetogenic effect of SARS-COV-2 (Severe Acute respiratory syndrome coronavirus).

Analysis of perioperative glucose metabolism using an artificial pancreas

Hyperglycemia associated with insulin resistance is common in surgical patients with and without diabetes and is associated with poor surgical outcomes. Several studies have recently shown that a closed-loop blood glucose monitoring system in the form of an artificial pancreas is safe and effective for surgical patients. In this study, we analyzed the risk factors for insulin resistance in patients using an artificial pancreas. We investigated 109 patients who underwent surgical management by an artificial pancreas for 24hours from the start of surgery during either major hepatectomy (MH), defined as resection of more than two liver segments, or pancreaticoduodenectomy (PD). The target glucose range was from 80 to 110mg/dL using an artificial pancreas. We analyzed the risk factors for and predictors of a high insulin dose, including sarcopenia markers, according to the median 24-hour total insulin infusion. The median total insulin dose and glycemic control rate (GCR), which is the rate of achieving the target blood glucose range, per 24hours were 78.0IU and 30.4% in the MH group and 82.6IU and 23.5% in the PD group, respectively. The muscle volume was the only independent factor in the high-dose subgroup, and the GCR was significantly lower in the high-dose subgroup despite a high insulin dose in both the MH and PD groups. The results of this study suggest that preoperative sarcopenia is closely associated with insulin resistance in the perioperative period. Clinicians must effectively manage sarcopenia, which may result in improved perioperative glycemic control and reduced postoperative complications.

Diabetes and Tuberculosis: Is There a Relationship?

Background: There is growing evidence that Diabetes Mellitus (DM) is an important risk factor for Tuberculosis (TB) and might affect disease presentation and treatment response. Risk factors for TB include HIV/AIDS, immune suppression (i.e. steroids), silicosis, malnutrition, smoke from domestic stoves and cigarettes, and DM. In recent decades, TB incidence has declined in high-income countries, but incidence remains high in countries that have high rates of HIV infection, malnutrition, and crowded living conditions. Furthermore, DM prevalence is increasing globally, fueled by obesity. Several case–control studies have shown that the odd ratios of developing TB in diabetic patients ranges from 2.44 to 8.33 compared with non-diabetic patients. Several large-scale longitudinal cohort studies have shown similar findings. Case: A 63-year-old male with poorly controlled type 2 DM (HbA1C of 15%), HTN, COPD and history of pulmonary TB who had previously received 2 courses of treatment, was admitted with sudden dyspnea with non-productive cough. In the ED, he was hypoxic, had bilateral pleural effusions, lower extremity edema and newly diagnosed acute systolic CHF. Sputum smear analysis was AFB positive and Mycobacterium tuberculosis was confirmed via PCR. The smear microbes were resistant to rifampin, poor sample limited further sensitivities, and the patient was started on empiric treatment for multi drug resistant TB with RIPE, Capreomycin, Linezolid, and Moxifloxacin. Endocrinology was consulted to assist in control of hyperglycemia. The patient was managed with high doses of insulin. At the time of discharge his blood glucose where in the range of 120–180 mg/dl during the entire day and the importance of having good BG control was reinforced. He continues his treatment for TB. Discussion: Diabetes leads to increased susceptibility to Mycobacterium tuberculosis infection and disease via multiple mechanisms, including those directly related to hyperglycemia, as well as indirectly via the effect on macrophage and lymphocyte function, leading to diminished ability to contain the organism. It is possible the refractory course of this patient’s TB and subsequent development of MDR disease was in part due to his poorly controlled diabetes due to poor compliance to prior regimens. Conclusion: DM is associated with increased risk of contracting TB, the possible delay in sputum culture conversion, increased mortality, and increased risk of recurrent and refractory disease. Adequate screening and treatment of DM may be essential to help prevent patients with diabetes from contacting the disease especially in countries with high prevalence of TB. Also, it is important to ensure adequate treatment response and prevent the development of multidrug resistant disease in diabetics who have already contracted TB.

Schmidt’s Syndrome Presenting as Diabetic Ketoacidosis and Adrenal Crisis: A Case Report and Review of Literature

Introduction: Schmidt’s Syndrome, is a rare endocrine disorder defined by the combined occurrence of Addison disease, autoimmune thyroid disease, and type 1 diabetes mellitus. The rarity of the condition and the presentation of adrenal insufficiency and hypothyroidism often lead to misdiagnosis with life-threatening consequences for the patients. We report a case presenting with adrenal insufficiency and diabetic ketoacidosis who was diagnosed with Schmidt’s Syndrome. Case Description: We describe the case of a 38-year-old male with a past medical history of hypothyroidism, who was admitted for worsening abdominal pain, nausea, vomiting, fevers, and chills. Physical exam revealed underweight male with marked dehydration, diaphoresis, in moderate abdominal pain. Initial vital signs and laboratory panel raised suspicion for adrenal insufficiency and diabetic ketoacidosis. Blood pressure 82/42mmHg, HR of 121, sodium 128mmol/L, potassium 6.8mmol/L, chloride 104mmol/L, bicarbonate 5mmol/L, BUN 20mg/dl, Creatinine 1.5mg/dl, Glucose 402mg/dl, TSH 60, and serum osmolality 319mosm/kg. The electrolyte derangements and vital signs improved after the initiation of the high-dose steroids and insulin. The patient was transitioned to a regimen of hydrocortisone/ fludrocortisone, levothyroxine, and insulin basal/bolus and was discharged in clinically stable conditions to follow up with an endocrinologist. Discussion: The prevalence of Schmidt’s syndrome is 1:20,000 in the general population and a 3:1 ratio of females to males. Autoimmune thyroid disease is present in 70–75%, T1DM in 40–60%, and Addison’s disease in 40–50%. This syndrome can be associated with other non-endocrine autoimmune disorders, such as vitiligo, myasthenia gravis, Sjogren’s syndrome, rheumatoid arthritis, and primary antiphospholipid syndrome. The initial step in diagnosis should be checking serum morning cortisol levels to identify adrenal insufficiency. Autoimmune antibodies play an important role to confirm the diagnosis including 21-hydroxylase, 17-hydroxylase, thyroid peroxidase, glutamic acid decarboxylase, islet cells, anti-tissue transglutaminase antibodies, parietal cell, and anti-intrinsic factor antibodies. Currently, treatment is limited to hormone replacement in patients with organ failure. But it is crucial to replace corticosteroids before starting thyroid replacement in patients with adrenal insufficiency. Conclusion: A high level of diagnostic suspicion is required for the diagnosis of Schmidt’s syndrome when encountering a patient with autoimmune disease. The diagnosis of this syndrome is often delayed, causing adverse events. With this case presentation, we add to the data pool of Schmidt’s syndrome with the ability to significantly improve patients outcomes with early diagnosis and hormone replacement.

Extreme High Insulin Requirements in Two Non-Diabetic Patients Following Cardiac Transplantation

Introduction: Blood glucose (BG) management is challenging following cardiac transplantation (CT) due to insulin resistance (IR) induced by post-operative stress and inflammation, intravenous pressors, and high-dose steroids. Severe IR manifested by extreme insulin requirements is rare. We report 2 such patients without prior history of diabetes (DM) requiring massive doses of IV insulin in the immediate post-op period. Patient 1: A 59 y/o male with hypertrophic cardiomyopathy (CM) presented with symptoms of acute decompensated heart failure and ultimately underwent orthotopic CT. At baseline, HbA1c was 5.8% and BMI 23 kg/m2. Exam was significant for acanthosis nigricans. He received 1g IV methylprednisolone (MP) during surgery and 125 mg IV Q 8 hours subsequently. His blood glucose (BG) immediately post-op was 312 mg/dL and was started on IV insulin. Despite doses up to 93 U/hr, BG remained >300mg/dl. With steroid taper, insulin requirements declined rapidly. He was transitioned to small dose of insulin glargine and was discharged on metformin monotherapy with near-normal BGs. Patient 2: 49 y/o male with a genetic CM was admitted for elective orthotopic CT. At baseline, HbA1c was 5.8% and BMI 32 kg/m2. Exam was significant for central obesity. He received similar doses of IV MP as patient 1 but also required inotropes (dobutamine, epinephrine, milrinone mixed in 5% dextrose containing fluids.) His BG immediately post-op was 284 mg/dL and was started on IV insulin. Despite doses up to 85 U/hr, BG remained >250 mg/dl. With steroid taper, insulin requirements resolved rapidly and he was discharged with normal BGs off all DM agents. Pseudo insulin resistance (i.e. line occlusion or erroneous IV insulin solution concentration) was excluded in both cases. Conclusion: Although many patients require high insulin doses after CT, rarely are infusion rates as high as in our patients achieved, particularly in non-diabetic individuals. We propose that it was the combination of underlying IR/prediabetes, counter-regulatory hormones, proinflammatory cytokines, increased lipolysis, with exogenous steroids and catecholamine-based inotropic agents that resulted in extreme inhibition of insulin action. However, because this combination of factors is not necessarily rare in post-CT patients, other factors must have been at play and will remain to be elucidated. From a pragmatic standpoint, because of rapid decrease in BG levels as steroids were tapered, we recommend very close follow-up of such patients with rapid decreases in insulin infusion rates as necessitated by trends in prevailing glycemia to prevent hypoglycemia. It would also be helpful to target a slightly higher glucose goal in such patients to prevent subsequent hypoglycemia.

Intravenous Insulin Resistance in a Critically Ill Patient Secondary to Decreased Peripheral Perfusion

Introduction: Intravenous (IV) insulin infusion is the preferred treatment modality for hyperglycemia in the intensive care unit (ICU) due to its short duration of action and easy titratability. However, administration of IV insulin has challenges. These include frequent monitoring, site infiltration, and high insulin dose requirements with other ICU medications such as epinephrine. There are, however, limited reports demonstrating an elevated insulin requirement due to poor peripheral perfusion. Below illustrates such a case, necessitating a change from peripheral to central IV insulin administration. Case Presentation: A 50 year old male with well controlled type 2 diabetes and previous aortic valve replacement presented to our facility for prosthetic valve endocarditis complicated by aortic root abscess. He was admitted to the ICU, treated with IV antibiotics, abscess washout and aortic valve replacement. Preoperatively, he was started on IV regular insulin via continuous infusion through a central line. During the pre and intraoperative periods, his hourly IV insulin requirement ranged from 2.4 to 5 units/ hour (hr). His blood glucose (BG) ranged from 107-251mg/dL (n 70-99mg/dL). The patient became hypotensive intraoperatively requiring vasopressor support. Dobutamine and norepinephrine infusions were started via central access and were continued postoperatively at steady rates. Vasopressin was added through central access as the patient failed to meet hemodynamic targets. Postoperatively, the propofol infusion was discontinued and the IV regular insulin infusion was moved to the peripheral line where the propofol had previously been administered. BG increased steadily to a maximum of 402 mg/dL despite an increase in the peripheral IV insulin rate to 152.4 units/hr. The site of the IV insulin drip was changed to another solitary peripheral access without success in decreasing the IV insulin infusion rate. The elevated requirements were deemed secondary to the patient’s lack of peripheral perfusion and should decrease with transition to a central line. A preemptive decrease in insulin drip rate to 10% of the peripheral dose was used to avoid hypoglycemia. The insulin drip was changed to a central access with a rate of 15units/ hr. BG values declined to a range of 140 -180 mg/dL. The patient remained on the multiple vasopressors for hemodynamic support, however, the insulin drip was able to be decreased and ultimately, discontinued. Conclusion: This case illustrates a unique challenge in the treatment of hyperglycemia with multifactorial shock and our approach to management. Elevated IV insulin requirements persisted despite stability in vasopressor dose, change to a solitary peripheral IV site, and lack of interfering medications in the treatment regimen. This is the first case to demonstrate a relationship between high IV insulin requirements and poor peripheral perfusion.

Primary Hyperaldosteronism in Pregnancy: A Case Report

Background: Primary aldosteronism (PA) is a renin-independent hypersecretion of aldosterone that remains an underdiagnosed etiology of hypertension. Less than 50 cases of primary hyperaldosteronism in pregnancy have been reported in literature that are associated with pregnancy complications including preeclampsia. Clinical Case: A 41-year-old female G9P4 at 32 weeks gestation was admitted for suspected preeclampsia due to elevated blood pressure during a routine prenatal visit. Her comorbidities include type 2 diabetes, uncontrolled hypertension, and preeclampsia in a previous pregnancy. Home medications included Lisinopril 10 mg once daily which was discontinued upon pregnancy and switched to Labetalol 400 mg twice daily and Nifedipine ER 30 mg daily. She was on a total of 220 units of insulin daily.On presentation, patient complained of anxiety but denied any headache, nausea, visual disturbances, chest pain, palpitations, muscle cramps, or fatigue. Her blood pressure was 180/100 mmHg with heat rate of 73. Laboratory values was notable for potassium: 2.8 mmol/L (n 3.5–5 mmol/L), bicarbonate: 28 mmol/L (n 24–31 mmol/L), and magnesium: 1.4 mEq/L (n 1.3–1.9 mEq/L). Liver function test and platelet count were normal. Spot protein-creatinine ratio was 0.3 (n 0–0.2). ECG was normal sinus rhythm with a heart rate of 82 without decreased T wave amplitude or U waves. She received three doses of oral 40 mEq potassium chloride over twelve hours and potassium level post repletion was 3.0 mmol/L.Initially, her hypokalemia was attributed to high insulin dose requirements. Despite down titration of insulin, patient continued to have hypokalemic episodes (nadir 2.7 mmol/L) refractory to oral and parenteral potassium supplementation. She remained hypertensive despite Labetalol 600 mg every 8 hours, Nifedipine ER 30 mg every 12 hours, with as needed hydralazine 10 mg IV pushes, and underwent urgent cesarean delivery. Uncontrolled hypertension persisted postpartum with recurrent episodes of hypokalemia. Further investigations revealed a plasma aldosterone concentration (PAC) and plasma renin activity (PRA) levels of 43.5 ng/dL (n <10 ng/dL) and 1.67 ng/mL/hr (n 0.17–5.38 ng/mL/hr) respectively, potassium at time of testing was 3.6 mmol/L. PAC to PRA ratio was greater than 20:1 with an absolute PAC greater than 15 ng/dL, which is highly suggestive of PA. Conclusion: We present a case of suspected PA with spontaneous hypokalemia potentially masked by the use of ACE inhibitors uncovered during pregnancy. Given the changes to the renin-angiotensin-aldosterone system (RAAS) during pregnancy, the diagnosis of PA is difficult to establish during gestation. Still, little is known on how to optimally treat these patients. Reference: Morton, A., 2015. Primary Aldosteronism and Pregnancy. Pregnancy and hypertension. An International Journal of Women’s Cardiovascular Health, Volume 5 Issue 4, 259–262.

Case Series: Exacerbation of Insulin Resistance With Active COVID 19 Infection

Background: Severe hyperglycemia due to insulin resistance is associated with increased mortality due to induction of pro-inflammatory cytokines, immunodepression, impairing cellular function and healing. We describe 6 patients admitted with COVID19 pneumonia complicated with DKA requiring high dose insulin infusion. # 1 19 yo African American (AA) male with history of pre-DM and obesity (BMI 41 kg/m2) presented with polyuria, polydipsia, obtunded and intubated in ER. Labs showed pH 7.35, serum sodium (Na) 138 mmol/L, potassium (K) 6.8 mmol/L, chloride (Cl) 85 mmol/L, bicarbonate (HCO3) 10 mmol/L, glucose 1140 mg/dL, lactate 1.4 mmol/L, anion gap (AG) 43, Beta Hydroxybutyrate (BOH) > 4.50 mmol/L. A1c 13.4%. Placed on insulin drip at 29.5 U/hr or 5.7 U/kg/hr. Discharged on Detemir 60 U TID and Novolog 20 U TID ac. # 2 55 yo female with T2DM and obesity (BMI 37.42 kg/m2) presented with shortness of breath, intubated for hypoxia in ER. Labs showed pH 7.21, serum Na 138 mmol/L, K 5.6 mmol/L, Cl 101 mmol/L, HCO3 13 mmol/L, glucose 557 mg/dL, lactate 5 mmol/L, AG 24, BOH > 0.27 mmol/L. A1c 7.8%. Placed on insulin drip at 23 U/hr or 5 U/kg/hr. Died from multiorgan failure on day 7. # 3 75 yo Hispanic female with T2DM, HCV, post liver-kidney transplant on immunosuppressants, HTN presented with weakness. Intubated on day 6 for hypoxemia. Placed on stress dose steroids for transplant failure. BMI 30 kg/m2. Labs on day 6 showed pH 6.98, serum Na 140 mmol/L, K 3.5 mmol/L, Cl 100 mmol/L, HCO3 20 mmol/L, glucose 590 mg/dL, AG 20, BOH 1.40 mmol/L. A1c 6.6% a year ago. Placed on insulin drip at 34 U/hr or 10.9 U/kg/hr. She developed ESRD requiring CRRT dialysis. She was made comfort care. Died on day 7. # 4 38 yo AA male with obesity (BMI 59.5 kg/m2) presenting with confusion, polyuria, polydipsia. Labs showed pH 7.22. serum Na 133 mmol/L, K 6.8 mmol/L, Cl 81 mmol/L, HCO3 15 mmol/L, glucose 1760 mg/dL, lactate 3.8 mmol/L, AG 37, BOH > 4.50 mmol/L. A1c 12.6%. Placed on insulin drip at 36 U/hr or 6 U/kg/hr. Discharged on Detemir 20 U qhs. # 5 27 yo AA female with T2DM, HTN and obesity (BMI 51 kg/m2), pituitary adenoma presented with seizures. Labs showed pH 7.15, serum Na 133 mmol/L, K 7.0 mmol/L, Cl 84 mmol/L, HCO3 7 mmol/L, serum glucose 951 mg/dL, lactate 1.6 mmol/L, AG 24, BOH >2.45 mmol/L. A1c >15%. Placed on insulin drip at 24 U/hr or 5 U/kg/hr. Died on day 5 from multiorgan failure. # 6 74 yo Hispanic female with T2DM, HTN and asthma presented with altered mental status. BMI 28 kg/m2. Labs showed pH 7.25, serum Na 155 mmol/L, K 4.6 mmol/L, Cl 125 mmol/L, HCO3 17 mmol/L, serum glucose 779 mg/dL, lactate 2.6 mmol/L, AG 13, BOH >2.45 mmol/L. A1c > 15%. Placed on insulin drip at 24 U/hr or 3.5 U/kg/hr. Died on day 5. Conclusion: Patients with DM and obesity admitted with Covid19 infection presented with severe insulin resistance and poor outcomes. Cconsideration should be given to assessing therapeutic interventions to enhance insulin sensitivity and improve outcomes.

Autoregulation of insulin receptor signaling through MFGE8 and the αvβ5 integrin

The role of integrins, in particular αv integrins, in regulating insulin resistance is incompletely understood. We have previously shown that the αvβ5 integrin ligand milk fat globule epidermal growth factor like 8 (MFGE8) regulates cellular uptake of fatty acids. In this work, we evaluated the impact of MFGE8 on glucose homeostasis. We show that acute blockade of the MFGE8/β5 pathway enhances while acute augmentation dampens insulin-stimulated glucose uptake. Moreover, we find that insulin itself induces cell-surface enrichment of MFGE8 in skeletal muscle, which then promotes interaction between the αvβ5 integrin and the insulin receptor leading to dampening of skeletal-muscle insulin receptor signaling. Blockade of the MFGE8/β5 pathway also enhances hepatic insulin sensitivity. Our work identifies an autoregulatory mechanism by which insulin-stimulated signaling through its cognate receptor is terminated through up-regulation of MFGE8 and its consequent interaction with the αvβ5 integrin, thereby establishing a pathway that can potentially be targeted to improve insulin sensitivity.

Role of Structured Education in Reducing Lypodistrophy and its Metabolic Complications in Insulin-Treated People with Type 2 Diabetes: A Randomized Multicenter Case-Control Study.

IntroductionIt is essential to use the correct injection technique (IT) to avoid skin complications such as lipohypertrophy (LH), local inflammation, bruising, and consequent repeated unexplained hypoglycemia episodes (hypos) as well as high HbA1c (glycated hemoglobin) levels, glycemic variability (GV), and insulin doses. Structured education plays a prominent role in injection technique improvement. The aim was to assess the ability of structured education to reduce (i) GV and hypos, (ii) HbA1c levels, (iii) insulin daily doses, and (iv) overall healthcare-related costs in outpatients with T2DM who were erroneously injecting insulin into LH.Methods318 patients aged 19–75 years who had been diagnosed with T2DM for at least 5 years, were being treated with insulin, were routinely followed by a private network of healthcare centers, and who had easily seen and palpable LH nodules were included in the study. At the beginning of the 6-month run-in period (T−6), all patients were trained to perform structured self-monitoring of blood glucose and to monitor symptomatic and severe hypos (SyHs and SeHs, respectively). After that (at T0), the patients were randomly and equally divided into an intervention group who received appropriate IT education (IG) and a control group (CG), and were followed up for six months (until T+6). Healthcare cost calculations (including resource utilization, loss of productivity, and more) were carried out based on the average NHS reimbursement price list.ResultsBaseline characteristics were the same for both groups. During follow-up, the intra-LH injection rate for the CG progressively decreased to 59.9% (p < 0.001), a much smaller decrease than seen for the IG (1.9%, p < 0.001). Only the IG presented significant decreases in HbA1c (8.2 ± 1.2% vs. 6.2 ± 0.9%; p < 0.01), GV (247 ± 61 mg/dl vs. 142 ± 31 mg/dl; p < 0.01), insulin requirement (− 20.7%, p < 0.001), and SeH and SyH prevalence (which dropped dramatically from 16.4 to 0.6% and from 83.7 to 7.6%, respectively; p < 0.001). In the IG group only, costs—including those due to the reduced insulin requirement—decreased significantly, especially those relating to SeHs and SyHs, which dropped to €25.8 and €602.5, respectively (p < 0.001).ConclusionWithin a 6-month observation period, intensive structured education yielded consistently improved metabolic results and led to sharp decreases in the hypo rate and the insulin requirement. These improvements resulted in a parallel drop in overall healthcare costs, representing a tremendous economic advantage for the NHS. These positive results should encourage institutions to resolve the apparently intractable problem of LH by financially incentivizing healthcare teams to provide patients with intensive structured education on proper injection technique.Trial RegistrationTrial registration no. 118/15.04.2018, approved by the Scientific and Ethics Committee of Campania University “Luigi Vanvitelli,” Naples, Italy, and by the institutional review board (IRB Min. no. 9926 dated 05.05.2018).Supplementary InformationThe online version contains supplementary material available at 10.1007/s13300-021-01006-0.

Clinical Impact of Initiation of U-500 Insulin vs Continuation of U-100 Insulin in Subjects With Diabetes.

The prevalence of obesity and diabetes mellitus (DM) has each increased drastically according to the Centers for Disease Control and Prevention. Growth of severe insulinresistant DM is predicted. U-500 insulin is highly concentrated and can replace less concentrated formulations in patients that need high insulin dosages. The aim of this study was to compare clinical outcomes of U-500 and U-100 insulin regimens in veterans with obesity and insulin resistance. A single-site retrospective chart analysis of adult subjects was conducted from July 2002 to June 2011. Data for repeated measures spanned a period from 3 months before the intervention (baseline) through 12 months afterward. The main outcome was the variation in hemoglobin A1c (HbA1c). Other outcomes included incidence of severe hypoglycemia, weight changes, cardiovascular events, and number of injections. A total of 142 subjects (68 taking U-500 and 74 taking U-100) were included. Baseline characteristics were similar between the groups, except for weight, which was higher among U-500 subjects. Mean HbA1c was reduced by 0.84% and 0.56% in U-500 and U-100, respectively (P = .003). Severe hypoglycemia occurred in 5 subjects in the U-500 group and 1 in the U-100 group (P = .08). No significant difference was noted in the number of cardiovascular events. The mean number of daily injections was 2 in the U-500 group, and 4 in the U-100 group (P < .001). U-500 insulin, when compared with U-100 insulin regimens, led to a statistically significant reduction in HbA1c and number of insulin injections. Additional research is necessary to assess the risk of severe hypoglycemia in U-500 users. Neither regimen was associated with increased cardiovascular risk.

Outcomes and adverse effects of extremely high dose insulin infusions in ICU patients.

Describe the characteristics, hospital course, and outcomes of adult ICU patients receiving extremely high dose insulin infusions compared to those with lower insulin requirements. Retrospective observational study of 128 adult ICU patients receiving IV insulin infusions at a large academic medical center. Extremely high dose insulin infusions were defined as maximum rate≥35units/h. The primary endpoint was rate of hypoglycemia (BG<70mg/dL) and time to glucose control. A post-hoc matching analysis was performed for baseline imbalances. Analysis included 32 patents with extremely high dose insulin infusions and 96 patients without, and most had a goal BG 100-150mg/dL. Patients in the extreme group were more likely to have type 2 diabetes, a higher median hemoglobin A1c, preadmission insulin, be admitted for a medical reason, and receive inpatient steroids. The extreme group were more likely to experience hypoglycemia (<70mg/dL, 63% v. 34%, p=0.005), longer time to glucose control (19.8h v. 5.7h, p<0.001) and higher mortality (34% v. 15%, p=0.014). ICU patients with extremely high dose insulin infusions had more hypoglycemia and took longer to achieve glucose targets compared to those with lower requirements. An individualized approach may be required for appropriate management.