Clinical Presentation and Diagnostic Approach to Hypoglycemia in Adults Without Diabetes Mellitus.

OBJECTIVE: To review the clinical presentation, causes, and diagnostic approach to spontaneous hypoglycemia in adults without diabetes mellitus. METHODS: A literature review was performed using the PubMed and Google Scholar databases. RESULTS: Hypoglycemia is uncommon in people who are not on glucose-lowering medications. Under normal physiologic conditions, multiple neural and hormonal counterregulatory mechanisms prevent the development of abnormally low levels of plasma glucose. If spontaneous hypoglycemia is suspected, the Whipple triad should be used to confirm hypoglycemia before pursuing further diagnostic workup. The Whipple criteria include the following: (1) low levels of plasma glucose, (2) signs or symptoms that would be expected with low levels of plasma glucose, and (3) improvement in those signs or symptoms when the level of plasma glucose increases. Spontaneous hypoglycemia can be caused by conditions that cause endogenous hyperinsulinism, including insulinoma, postbariatric hypoglycemia, and noninsulinoma pancreatogenous hypoglycemia. Spontaneous hypoglycemia can also be seen with critical illness, hepatic or renal dysfunction, hormonal deficiency, non-diabetes-related medications, and non-islet cell tumors. The initial diagnostic approach should begin by obtaining a detailed history of the nature and timing of the patient's symptoms, medications, underlying comorbid conditions, and any acute illness. A laboratory evaluation should be conducted at the time of the spontaneous symptomatic episode. Supervised tests such as a 72-hour fast or mixed-meal test may be needed to recreate the situation under which the patient is likely to experience symptoms. CONCLUSION: We provide an overview of the physiology of counterregulatory response to hypoglycemia, its causes, and diagnostic approaches to spontaneous hypoglycemia in adults.

Different FreeSurfer versions might generate different statistical outcomes in case-control comparison studies.

PURPOSE: Neuroimaging pipelines have long been known to generate mildly differing results depending on various factors, including software version. While considered generally acceptable and within the margin of reasonable error, little is known about their effect in common research scenarios such as inter-group comparisons between healthy controls and various pathological conditions. The aim of the presented study was to explore the differences in the inferences and statistical significances in a model situation comparing volumetric parameters between healthy controls and type 1 diabetes patients using various FreeSurfer versions. METHODS: T1- and T2-weighted structural scans of healthy controls and type 1 diabetes patients were processed with FreeSurfer 5.3, FreeSurfer 5.3 HCP, FreeSurfer 6.0 and FreeSurfer 7.1, followed by inter-group statistical comparison using outputs of individual FreeSurfer versions. RESULTS: Worryingly, FreeSurfer 5.3 detected both cortical and subcortical volume differences out of the preselected regions of interest, but newer versions such as FreeSurfer 5.3 HCP and FreeSurfer 6.0 reported only subcortical differences of lower magnitude and FreeSurfer 7.1 failed to find any statistically significant inter-group differences. CONCLUSION: Since group averages of individual FreeSurfer versions closely matched, in keeping with previous literature, the main origin of this disparity seemed to lie in substantially higher within-group variability in the model pathological condition. Ergo, until validation in common research scenarios as case-control comparison studies is included into the development process of new software suites, confirmatory analyses utilising a similar software based on analogous, but not fully equivalent principles, might be considered as supplement to careful quality control.

Hospital-Care Utilization and Medical Cost Patterns Among Patients With Insulin-Dependent Diabetes.

OBJECTIVE: Using claims data from an integrated payer-provider, we compared costs incurred by patients with insulin-dependent diabetes mellitus (IDDM) who received Hospital Inpatient/Observation/EmeRgency Department care (HIghER care) for diabetes-related events with those who did not receive such care to identify a target population for interventions in future studies. METHODS: A retrospective study pooled real-world claims data for IDDM (type 1 or type 2) between July 1, 2018, and June 30, 2019. Medical claims were used to calculate the total and diabetes-related allowed medical costs to the enterprise and per member per month costs. RESULTS: Medical and prescription drug coverage from 19 378 members was analyzed. Only 8.4% of the IDDM population received HIghER care but incurred 20% of medical expenses and nearly 40% of diabetes-related medical costs. For HIghER care patients, medical spending was higher in every inpatient and outpatient category (Wilcoxon 2-sample tests, all P < .0001). Non-diabetes-related prescription drug costs were greater in this group (Wilcoxon test, Z = 2.2879, P = .0221), whereas diabetes-related prescription drug costs were higher for non-HIghER care (Wilcoxon test, Z = -9.5918, P < .0001). In a longitudinal study of 29 602 patients over 24 months, previous-year receipt of HIghER care was a significant predictor of HIghER care the subsequent year (odds ratio, 3.28). CONCLUSION: Medical spending for patients receiving HIghER care was disproportionately high and greater in every inpatient and outpatient category. HIghER care receipt the previous year was highly predictive of HIghER care episodes the following year.

Endocrine Complications of Cystic Fibrosis: A Multisystem Disease of the Endocrine Organs.

Cystic fibrosis (CF) is one of the most common life-limiting genetic disorders. Although CF is typically considered primarily as a pulmonary disease, the CF conductance transmembrane regulator is present throughout the body. From an endocrine perspective, this multisystem disease manifests primarily in the pancreas as a unique form of diabetes (CF-related diabetes mellitus), as bone disease, and as reproductive health issues in people with CF. These complications have become ever more concerning to people with CF as treatment for pulmonary disease improves and lifespans lengthen, increasing the impact of nonpulmonary complications. Our understanding of the management of these concerns continues to evolve, and, although there are some effective treatments, there is great opportunity for continued investigation into the pathophysiology of the endocrine complications of CF and their treatment.

Measurement of Hypothalamic Glucose Under Euglycemia and Hyperglycemia by MRI at 3T.

PURPOSE: To evaluate the feasibility of using a clinical magnetic resonance (MR) system and MR spectroscopy (MRS) to measure glucose concentration changes in the human hypothalamus, a structure central to whole-body glucose regulation. SUBJECTS AND METHODS: A time series of MR spectra (semi-LASER, TE = 28 msec), localized to the bilateral hypothalamus (∼1.6 ml) were obtained at 3T in six healthy subjects at baseline (euglycemia) and during a ∼65-70-minute-long hyperglycemic clamp in 11-minute blocks with interleaved T1 FLASH images to retrospectively assess head motion, and track changes in cerebrospinal fluid (CSF) partial volume. The LCModel was used to quantify the sum of glucose and taurine concentrations, [Glc+Tau], along with their associated Cramér-Rao lower bounds (CRLB). RESULTS: Spectral quality allowed quantification of [Glc+Tau] (sum reported due to high negative correlation between these metabolites) with CRLB <25% in 35/36 timepoints during hyperglycemia. Increased [Glc+Tau] was observed with hyperglycemia in all subjects, but most reliably in those with plasma glucose targets ≥300 mg/dl. For these subjects, [Glc+Tau]baseline (n = 4) was 1.5 (±0.3, SD) mM, and increased to 4.5 (±1.1) mM (n = 16) for timepoints acquired ≥25 minutes after onset of the clamp, with 15/16 timepoints having no overlap of 95% confidence intervals (CIs) between baseline and hyperglycemia. Preliminary analysis revealed a linear (1:5) relationship between hypothalamus-blood glucose concentrations. CONCLUSION: It is feasible to measure glucose concentration changes in the human hypothalamus using a standard 3T scanner and a short-echo semi-LASER sequence by utilizing retrospective motion tracking, CSF correction, predetermined quality acceptance criteria, and hyperglycemic blood glucose levels ≥300 mg/dl. LEVEL OF EVIDENCE: 2 J. Magn. Reson. Imaging 2017;45:681-691.

Feasibility and reproducibility of neurochemical profile quantification in the human hippocampus at 3 T.

Hippocampal dysfunction is known to be associated with several neurological and neuropsychiatric disorders such as Alzheimer's disease, epilepsy, schizophrenia and depression; therefore, there has been significant clinical interest in studying hippocampal neurochemistry. However, the hippocampus is a challenging region to study using (1) H MRS, hence the use of MRS for clinical research in this region has been limited. Our goal was therefore to investigate the feasibility of obtaining high-quality hippocampal spectra that allow reliable quantification of a neurochemical profile and to establish inter-session reproducibility of hippocampal MRS, including reproducibility of voxel placement, spectral quality and neurochemical concentrations. Ten healthy volunteers were scanned in two consecutive sessions using a standard clinical 3 T MR scanner. Neurochemical profiles were obtained with a short-echo (T(E) = 28 ms) semi-LASER localization sequence from a relatively small (~4 mL) voxel that covered about 62% of the hippocampal volume as calculated from segmentation of T1 -weighted images. Voxel composition was highly reproducible between sessions, with test-retest coefficients of variation (CVs) of 3.5% and 7.5% for gray and white matter volume fraction, respectively. Excellent signal-to-noise ratio (~54 based on the N-acetylaspartate (NAA) methyl peak in non-apodized spectra) and linewidths (~9 Hz for water) were achieved reproducibly in all subjects. The spectral quality allowed quantification of NAA, total choline, total creatine, myo-inositol and glutamate with high scan-rescan reproducibility (CV ≤ 6%) and quantification precision (Cramér-Rao lower bound, CRLB < 9%). Four other metabolites, including glutathione and glucose, were quantified with scan-rescan CV below 20%. Therefore, the highly optimized, short-echo semi-LASER sequence together with FASTMAP shimming substantially improved the reproducibility and number of quantifiable metabolites relative to prior reports. In addition, the between-session variation in metabolite concentrations, as well as CRLB, was lower than the between-subject variation of the concentrations for most metabolites, indicating that the method has the sensitivity to detect inter-individual differences in the healthy brain.

Revisiting Glycogen Content in the Human Brain.

Glycogen provides an important glucose reservoir in the brain since the concentration of glucosyl units stored in glycogen is several fold higher than free glucose available in brain tissue. We have previously reported 3-4 µmol/g brain glycogen content using in vivo (13)C magnetic resonance spectroscopy (MRS) in conjunction with [1-(13)C]glucose administration in healthy humans, while higher levels were reported in the rodent brain. Due to the slow turnover of bulk brain glycogen in humans, complete turnover of the glycogen pool, estimated to take 3-5 days, was not observed in these prior studies. In an attempt to reach complete turnover and thereby steady state (13)C labeling in glycogen, here we administered [1-(13)C]glucose to healthy volunteers for 80 h. To eliminate any net glycogen synthesis during this period and thereby achieve an accurate estimate of glycogen concentration, volunteers were maintained at euglycemic blood glucose levels during [1-(13)C]glucose administration and (13)C-glycogen levels in the occipital lobe were measured by (13)C MRS approximately every 12 h. Finally, we fitted the data with a biophysical model that was recently developed to take into account the tiered structure of the glycogen molecule and additionally incorporated blood glucose levels and isotopic enrichments as input function in the model. We obtained excellent fits of the model to the (13)C-glycogen data, and glycogen content in the healthy human brain tissue was found to be 7.8 ± 0.3 µmol/g, a value substantially higher than previous estimates of glycogen content in the human brain.

Hypoglycemia mediated by paraneoplastic production of Insulin like growth factor-2 from a malignant renal solitary fibrous tumor - clinical case and literature review.

BACKGROUND: Hypoglycemic episodes are infrequent in individuals without a history of diabetes mellitus or bariatric surgery. When hypoglycemia does occur in such individuals, an uncommon but important diagnosis to consider is non-islet cell tumor hypoglycemia (NICTH). We report a case of NICTH associated with paraneoplastic insulin-like growth factor-2 (IGF-2) production and review current relevant medical literature. CASE PRESENTATION: A 60 year old male with no relevant past medical history was referred to the endocrinology clinic with 18 month history of episodic hypoglycemic symptoms and, on one occasion was noted to have a fingerstick glucose of 36 mg/dL while having symptoms of hypoglycemia. Basic laboratory evaluation was unrevealing. Further evaluation however showed an elevated serum IGF-2 level at 2215 ng/mL (reference range 411-1248 ng/mL). Imaging demonstrated a large right suprarenal mass. A right nephrectomy with resection of the mass demonstrated a malignant solitary fibrous tumor. Post resection, the patient's IGF-2 levels normalized and hypoglycemic symptoms resolved. CONCLUSION: Due to the structural and biochemical homology between IGF-2 and insulin, elevated levels of IGF-2 can result in hypoglycemia. A posttranslational precursor to IGF-2 known as "big IGF" also possesses biologic activity. Review of recent reported cases of NICTH identified widespread anatomic locations and varied pathologic diagnoses of tumors associated with paraneoplastic production of IGF-2 causing hypoglycemia. Definitive management of hypoglycemia associated with paraneoplastic production of IGF-2 consists of resection of the tumor responsible for IGF-2 production. Accumulating literature provides a firm basis for routine IGF-2 laboratory evaluation in patients presenting with spontaneous hypoglycemia with no readily apparent cause.

Experimental pharmacological approaches to reverse impaired awareness of hypoglycemia-a review.

The colossal global burden of diabetes management is compounded by the serious complication of hypoglycemia. Protective physiologic hormonal and neurogenic counterregulatory responses to hypoglycemia are essential to preserve glucose homeostasis and avert serious morbidity. With recurrent exposure to hypoglycemic episodes over time, these counterregulatory responses to hypoglycemia can diminish, resulting in an impaired awareness of hypoglycemia (IAH). IAH is characterized by sudden neuroglycopenia rather than preceding cautionary autonomic symptoms. IAH increases the risk of subsequent sudden and severe hypoglycemic episodes in patients with diabetes. The postulated causative mechanisms behind IAH are complex and varied. It is therefore challenging to identify a single effective therapeutic strategy. In this review, we closely examine the efficacy and feasibility of a myriad of pharmaceutical interventions in preventing and treating IAH as described in clinical and preclinical studies. Pharmaceutical agents outlined include N-acetyl cysteine, GABA A receptor blockers, opioid receptor antagonists, AMP activated protein kinase agonists, potassium channel openers, dehydroepiandrosterone, metoclopramide, antiadrenergic agents, antidiabetic agents and glucagon.

Hypoglycemia as a driver of cardiovascular risk in diabetes.

Severe hypoglycemia in patients with diabetes is associated with increased risk of adverse cardiovascular events and death. Recent large randomized clinical trials in individuals with type 2 diabetes have shown that intensive glycemic control may result in increased mortality, and hypoglycemia has been investigated as a possible cause. Acute hypoglycemia is a proarrhythmic, proinflammatory, and prothrombotic state, and several mechanisms have been proposed to explain how hypoglycemia might increase cardiovascular morbidity and mortality. However, data from large clinical trials do not provide strong evidence to establish hypoglycemia as a cause of increased mortality. Severe hypoglycemia is also a marker of frailty and a predictor of adverse outcomes in patients with diabetes. Individualized therapy should be the goal in patients with diabetes to avoid severe hypoglycemia and any related adverse outcomes.

A rare case of isolated IgG4-related hypophysitis with Rathke's cleft cyst presenting as panhypopituitarism.

Summary: We report a rare case of biopsy-proven isolated immunoglobulin G4 (IgG4)-related hypophysitis and Rathke's cleft cyst (RCC) presenting as panhypopituitarism. A 54-year-old Caucasian female presented with symptoms of slurred speech, altered mental status, polyuria and polydipsia and was found to have panhypopituitarism. Brain MRI showed a suprasellar mass with suspected intralesional hemorrhage. She underwent trans-sphenoidal resection due to MRI evidence of compression of the optic chiasm and left optic nerve. Preoperatively, she was started on hydrocortisone, levothyroxine and desmopressin. Histopathology demonstrated a RCC with adjacent lymphoplasmacytic hypophysitis with numerous IgG4-immunoreactive plasma cells. Hydrocortisone was stopped at 10 months after confirming hypothalamic-pituitary-adrenal (HPA)-axis recovery and desmopressin was stopped at 1 year. There was recurrence of a cystic mass at 1 year follow-up. Over 4 years of follow-up, she continued to require levothyroxine, and the mass remained stable in size. In order to begin to understand how this case's unique histopathological presentation influences clinical presentation, pituitary imaging and prognosis, we present an accompanying literature review. Learning points: Isolated IgG4 hypophysitis and coexisting Rathke's cleft cyst is a rare condition, which presents a diagnostic challenge. Recognizing its characteristic features can assist with early recognition and initiation of therapy to promote optimal outcomes. Further studies investigating the mechanisms promoting co-occurrence of these entities and their effect on prognosis are needed.

The impact of elexacaftor/tezacaftor/ivacaftor on body composition in a small cohort of youth with cystic fibrosis.

BACKGROUND: The effects of elexacaftor-tezacaftor-ivacaftor (ETI) on body composition in people with CF (pwCF) are unknown. METHODS: Dual-energy X-ray absorptiometry fat-free mass and fat mass adjusted for height (FMI) as well as oral glucose tolerance test derived measures of insulin secretion and sensitivity were compared before and after ETI initiation in eight pwCF. RESULTS: Patients median age: 22 years interquartile range (IQR: 16-28), 87.5% male, median time on ETI:11 months. Weight z-score increased from -0.52 to 0.18 (p = 0.014); FMI increased from 4.12 to 6.29 (p = 0.014). Insulin secretion (C pep iAUC/Gluc iAUC) increased from 8.71 to 14.21 (p = 0.021), insulin resistance (HOMA2 IR) increased from 0.73 to 1.25 (p = 0.014) and insulin sensitivity decreased (Matsuda) 8.88 to 5.58 (p = 0.036). CONCLUSIONS: ETI resulted in increased weight and fat mass. BMI and muscle mass did not change. Both insulin secretion and insulin resistance increased. Longer-term metabolic consequences of ETI need further investigation.

Population Pharmacokinetic Model of N-Acetylcysteine During Periods of Recurrent Hypoglycemia in Healthy Volunteers.

Recurrent hypoglycemia leads to impaired awareness of hypoglycemia where the blood glucose threshold that elicits the counterregulatory response is lowered. Hypoglycemia-induced oxidative stress is hypothesized to contribute to impaired awareness of hypoglycemia development and hypoglycemia-associated autonomic failure. Our group conducted a randomized, double-blinded, placebo-controlled, crossover study in healthy individuals undergoing experimentally induced recurrent hypoglycemia to evaluate the impact of intravenous N-acetylcysteine (NAC) during experimental hypoglycemia to preserve the counterregulatory response to subsequent hypoglycemia. The work presented herein aimed to characterize the NAC pharmacokinetics and its effects on oxidative stress. Whole blood and plasma samples were collected at specified time points during separate NAC and placebo infusions from 10 healthy volunteers. Samples were analyzed for NAC, cysteine, and glutathione (GSH) concentrations. A 2-compartment population NAC pharmacokinetic model was developed. Estimates for central compartment clearance and volume of distribution were 19.8 L/h, and 12.2 L, respectively, for a 70-kg person. Peripheral compartment clearance and volume of distribution estimates were 34.9 L/h and 13.1 L, respectively, for a 70-kg person. The PK parameters estimated here were different from those reported in the literature, suggesting a higher NAC clearance during hypoglycemic episodes. NAC leads to a significant increase in circulating cysteine concentration in a NAC concentration-dependent manner, suggesting rapid biotransformation. A transient decrease in plasma GSH was observed, supporting the hypothesis that NAC can act as a reducing agent displacing glutathione from the disulfide bond allowing for increased clearance and/or distribution of GSH.

New Concepts in the Pathogenesis of Cystic Fibrosis-Related Diabetes.

CONTEXT: Cystic fibrosis-related diabetes (CFRD) is the most common extrapulmonary complication of cystic fibrosis (CF). Approximately 40% of people with CF who are older than 20 years have CFRD. Presence of CFRD is associated with poor health outcomes in people with CF. OBJECTIVE: This review summarizes current knowledge on pathophysiology of CFRD. METHODS: A PubMed review of the literature was conducted, with search terms that included CFRD, cystic fibrosis, cystic fibrosis related diabetes, and cystic fibrosis transmembrane conductance regulator (CFTR). Additional sources were identified through manual searches of reference lists. Pathophysiology of CFRD: The pathophysiology underlying development of glucose tolerance abnormalities in CF is complex and not fully understood. ß-cell loss and functional impairment of the remaining ß-cell function results in progressive insulin insufficiency. Factors that may contribute to development of CFRD include local islet and systemic inflammation, alterations in the incretion hormone axis, varying degrees of insulin resistance and genetic factors related to type 2 diabetes. CONCLUSION: The prevalence of CFRD is expected to further increase with improving life expectancy of people with CF. Further research is needed to better understand the mechanisms underlying the development of CFRD and the impact of diabetes on clinical outcomes in CF.

The Effect of Control IQ Hybrid Closed Loop Technology on Glycemic Control in Adolescents and Adults with Cystic Fibrosis-Related Diabetes.

Background: Cystic fibrosis-related diabetes (CFRD) is associated with pulmonary decline, compromised nutritional status, and earlier mortality. Although diabetes technology is increasingly being used in individuals with CFRD, there is a paucity of data investigating the impact of hybrid closed loop (HCL) technology on glycemia in this patient population. Materials and Methods: In this multicenter retrospective study of 13 adults and adolescents with CFRD, 14 days of continuous glucose monitor data were analyzed at baseline, 1 and 3 months after transition to the Tandem t:slim X2 pump with Control IQ™ technology, a HCL system. Results: Control IQ initiation was associated with a significant increase in % time in target range (70-180 mg/dL), as well as decreases in average glucose, % time in hyperglycemic ranges (% time >180 mg/dL, % time >250 mg/dL), and glycemic variability (standard deviation, coefficient of variation). There was no significant change in % time in hypoglycemia ranges (% time <54 mg/dL, % time <70 mg/dL). Conclusions: To our knowledge, this is the first study to report a beneficial effect of Food and Drug Administration (FDA)-approved HCL technology on glycemia in adults and adolescents with CFRD to date. Future studies are needed to understand the potential long-term glycemic benefits of HCL devices and to explore the impact of this technology on heath-related quality of life, pulmonary function, nutritional status, and mortality.

Relationship Between Hypoglycemia Awareness Status on Clarke/Gold Methods and Counterregulatory Response to Hypoglycemia.

Context: Impaired awareness of hypoglycemia (IAH) is characterized by the diminished ability to perceive symptoms of hypoglycemia. Gold and Clark questionnaires are commonly used to identify patients with IAH. The relationship between IAH status on questionnaires and a person's symptom and epinephrine responses to hypoglycemia are not well understood. Objective: We aimed to examine the relationship between hypoglycemia awareness status on Clarke and Gold questionnaires with both hormonal and symptomatic responses to experimental hypoglycemia. Methods: In this university medical center study, we examined data from 78 subjects with type 1 diabetes (T1D) who completed both questionnaires and underwent a hyperinsulinemic hypoglycemic clamp (target glucose 50 mg/dL). Results: Clarke and Gold scores were highly correlated with one another (r = 0.82) and each had a moderate negative relationship with epinephrine (Clarke: r = -0.51, Gold: r = -0.50) and total symptom response (Clarke: r = -0.59, Gold: r = -0.57). However, 32% of the subjects were classified inconsistently by Clark vs Gold. A clustering analysis was done to examine how disagreement between the 2 questionnaires on IAH classification relates to epinephrine and symptoms responses during hypoglycemia. Subjects who had partial loss of symptoms or of epinephrine response were more likely to be classified inconsistently. Conclusion: Our results show that IAH classification may be discordant between Clark and Gold questionnaires and that hypoglycemia awareness status on Clarke and Gold questionnaires poorly predicts hormonal and symptomatic responses to hypoglycemia in subjects with T1D and moderate blunting of symptoms or epinephrine.

Heterogeneity in Epinephrine Response to Experimental Hypoglycemia in Type 1 Diabetes and Controls.

Context: The epinephrine response (Epi) to a first episode of hypoglycemia (HG) has been proposed to be predictive of Epi in subsequent HG and to provide insight into the risk for developing HG-associated autonomic failure (HAAF) in healthy controls (HCs). Objective: To determine if Epi and symptom response (SR) to the first episode of HG predicts who will develop HAAF after exposure to recurrent HG in volunteers with type 1 diabetes (T1D) and in HCs. Design: Review of data collected between 2013 and 2019. Setting: Academic clinical research unit. Patients or Participants: Volunteers with T1D and HCs. Interventions: Subjects participated in a preinduction protocol where they were exposed to three 2-hour episodes of clamped HG over 2 days. Data collected during clamp 1 were compared with data collected during clamp 3. Main outcome measure: Difference in Epi and SR. Results: Using the standard definition of HAAF in which HG-induced Epi during clamp 3 is at least 20% lower than during clamp 1, 21/28 HCs and 13/19 volunteers with T1D developed HAAF. Epi during clamp 1 was significantly higher in those subjects who developed HAAF than in those who did not in both groups (P = 0.02). If HAAF is defined as achieving a 20% reduction in HG-induced SR measured during clamp 3 compared with clamp 1, 10/27 HCs and 10/19 volunteers with T1D developed SR-based HAAF. Conclusion: There was heterogeneity in the response to the preinduction protocol. Epi during clamp 1 was higher than in clamp 3 in HCs and in those with T1D who developed HAAF.

Coronary artery disease in patients with cystic fibrosis - A case series and review of the literature.

Progressive obstructive pulmonary disease is the primary life-shortening complication in people with Cystic Fibrosis (CF); improvement in life expectancy has led to increased prevalence of non-pulmonary complications. Patients with CF are considered to be at low risk for coronary artery disease (CAD). We report here a case series of six patients with CF with and without known cystic fibrosis related diabetes (CFRD) who had acute myocardial infarction (AMI) requiring coronary stent placement. This was a heterogeneous group of patients, without a clear pattern of consistent risk factors. Interestingly, most patients in this cohort had low LDL. In this review, we discuss risk factors of cardiovascular disease (CVD) that may apply to the CF population. While CAD is rare in people with CF, it does occur. We postulate that the risk will grow with increased longevity and the increased prevalence of co-morbidities such as obesity and dyslipidemia.

Glycemia and ß-cell function before and after elexacaftor/tezacaftor/ivacaftor in youth and adults with cystic fibrosis.

Background: Diabetes is prevalent among people with CF (PwCF) and associated with worse clinical outcomes. CFTR modulators are highly effective in improving the disease course of CF. However, the effects of elexacaftor/tezacaftor/ivacaftor (ETI) on glucose metabolism in PwCF are unclear. Methods: Twenty youth and adults with CF underwent frequently sampled oral glucose tolerance tests (fsOGTT) before and after ETI initiation. Glucose, insulin, and C-peptide were collected at 0, 10, 30, 60, 90, and 120 min after 1.75 g/kg (max 75 g) of dextrose. HbA1c and continuous glucose monitoring (CGM) were collected in a subset. Estimates of insulin secretion (C-peptide index), insulin resistance (HOMA2 IR and IS(OGTT Cpep)), and ß-cell function (C-peptide oral disposition index, oDIcoeo), were compared before and after ETI. Results: Participants were a median (IQR) of 20.4 (14.1, 28.6) years old, 75 % male. Follow-up occurred 10.5 (10.0, 12.3) months after ETI initiation. BMI z-score increased from 0.3 (-0.3, 0.8) to 0.8 (0.4, 1.5), p = 0.013 between visits. No significant differences were observed in glucose tolerance, glucose area under the curve, nor fsOGTT glucose concentrations before and after ETI. Median (IQR) C-peptide index increased from 5.7 (4.1, 8.3) to 8.8 (5.5, 10.8) p = 0.013 and HOMA2 IR increased (p < 0.001), while oDIcoeo was unchanged (p = 0.67). HbA1c decreased from 5.5 % (5.5, 5.8) to 5.4 % (5.2, 5.6) (p = 0.003) while CGM variables did not change. Conclusions: BMI z-score and measures of both insulin resistance and insulin secretion increased within the first year of ETI initiation. ß-cell function adjusted for insulin sensitivity (oDIcoeo) did not change.

Obesity in cystic fibrosis.

The prevalence of obesity in patients with cystic fibrosis (CF) is increasing and around one-third of adults with CF are now overweight or obese. The causes of excess weight gain in CF are likely multifactorial, including: adherence to the high-fat legacy diet, reduced exercise tolerance, therapeutic advances, and general population trends. Increased weight has generally been considered favorable in CF, correlating with improved pulmonary function and survival. While the optimal BMI for overall health in CF is unknown, most studies demonstrate minimal improvement in pulmonary function when BMI exceeds 30 kg/m2. Dyslipidemia and cardiovascular disease are important co-morbidities of obesity in the general population, but are uncommon in CF. In people with CF, obesity is associated with hypertension and higher cholesterol levels. With longer life expectancy and rising obesity rates, there may be an increase in cardiovascular disease among people with CF in coming years. Overweight CF patients are more likely to be insulin resistant, taking on features of type 2 diabetes. Treating obesity in people with CF requires carefully weighing the metabolic risks of overnutrition with the impact of low or falling BMI on lung function. This article describes current knowledge on the epidemiology, causes, consequence, and treatment of obesity in people with CF.