Faculty Bibliography

INTRODUCTION/BACKGROUND:Sodium-glucose cotransporter-2 [SGLT2] inhibitors reduce cardiovascular events and mortality in patients with diabetes, particularly patients with established cardiovascular disease. Euglycemic diabetic ketoacidosis [euDKA], a complication of SGLT2 therapy, can be exacerbated by a low carbohydrate diet. CASE REPORT/METHODS:A 61-year-old man with a history of type 2 diabetes, taking a SGLT2 inhibitor empagliflozin 10 mg orally daily, presented to the emergency room with a 2-day history of nausea and chest pain. A week prior to presentation, he had started a ketogenic diet. He was initially admitted with a diagnosis of acute coronary syndrome. On initial assessment in the emergency room, his cardiac enzymes were normal and there were no ischemic changes in his ECG. As there was concern for unstable angina, he underwent cardiac catheterization, which showed a known total occlusion with collaterals and arteries with non-obstructive disease without evidence of acute plaque rupture. His baseline laboratory assessments revealed an elevated anion gap of 17, increased urinary and plasma ketones, and metabolic acidosis. His plasma glucose level was 84 mg/dL. The diagnosis of euDKA was made, and treatment with intravenous fluids and insulin was initiated. His chest pain and nausea subsequently resolved. CONCLUSION/CONCLUSIONS:We present a case of euDKA triggered by a ketogenic diet while on SGLT2 inhibitor therapy presenting as chest pain. The recognition of euDKA is important in the context of increased SGLT2 use for management of cardiovascular risk for patients with diabetes.

Many healthcare providers screen high-risk individuals exclusively with an HbA1c despite its insensitivity for detecting dysglycemia. The two cases presented describe the inherent caveats of interpreting HbA1c without performing an oral glucose tolerance test (OGTT). The first case reflects the risk of over-diagnosing type 2 diabetes (T2D) in an older African American male in whom HbA1c levels, although variable, were primarily in the mid- prediabetes range (5.7-6.4% [39-46 mmol/mol]) for many years although the initial OGTT demonstrated borderline impaired fasting glucose (IFG) with a fasting plasma glucose (FPG) of 102 mg/dl [5.7 mmol/L]) without evidence for impaired glucose tolerance (IGT) (2-hour glucose >140-199 mg/dl ([7.8 -11.1 mmol/L]). As subsequent HbA1c levels were diagnostic of T2D (6.5-6.6% [48-49 mmol/mol]), a second OGTT performed was normal. The second case illustrates the risk of under-diagnosing T2D in a male with HIV having normal HbA1c levels over many years who underwent an OGTT when mild prediabetes [HbA1c = 5.7% (39 mmol/mol)] developed which was diagnostic of T2D. To avoid inadvertent mistreatment, it is therefore essential to perform an OGTT, despite its limitations, in high-risk individuals particularly when glucose or fructosamine and HbA1c values are discordant. Innate differences in the relationship between fructosamine or fasting glucose to HbA1c are demonstrated by the glycation gap or hemoglobin glycation index.

Quality Improvement Success Stories are published by the American Diabetes Association in collaboration with the American College of Physicians, Inc., and the National Diabetes Education Program. This series is intended to highlight best practices and strategies from programs and clinics that have successfully improved the quality of care for people with diabetes or related conditions. Each article in the series is reviewed and follows a standard format developed by the editors of Clinical Diabetes. The following article describes the establishment of a Diabetes Prevention Clinic for veterans with prediabetes.

Prediabetes (intermediate hyperglycemia) consists of two abnormalities, impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) detected by a standardized 75-gram oral glucose tolerance test (OGTT). Individuals with isolated IGT or combined IFG and IGT have increased risk for developing type 2 diabetes (T2D) and cardiovascular disease (CVD). Diagnosing prediabetes early and accurately is critical in order to refer high-risk individuals for intensive lifestyle modification. However, there is currently no international consensus for diagnosing prediabetes with HbA1c or glucose measurements based upon American Diabetes Association (ADA) and the World Health Organization (WHO) criteria that identify different populations at risk for progressing to diabetes. Various caveats affecting the accuracy of interpreting the HbA1c including genetics complicate this further. This review describes established methods for detecting glucose disorders based upon glucose and HbA1c parameters as well as novel approaches including the 1-hour plasma glucose (1-h PG), glucose challenge test (GCT), shape of the glucose curve, genetics, continuous glucose monitoring (CGM), measures of insulin secretion and sensitivity, metabolomics, and ancillary tools such as fructosamine, glycated albumin (GA), 1,5- anhydroglucitol (1,5-AG). Of the approaches considered, the 1-h PG has considerable potential as a biomarker for detecting glucose disorders if confirmed by additional data including health economic analysis. Whether the 1-h OGTT is superior to genetics and omics in providing greater precision for individualized treatment requires further investigation. These methods will need to demonstrate substantially superiority to simpler tools for detecting glucose disorders to justify their cost and complexity.

For over 100 years, the oral glucose tolerance test (OGTT) has been the cornerstone for detecting prediabetes and type 2 diabetes (T2DM). In recent decades, controversies have arisen identifying internationally acceptable cut points using fasting plasma glucose (FPG), 2-h post-load glucose (2-h PG), and/or HbA1c for defining intermediate hyperglycemia (prediabetes). Despite this, there has been a steadfast global consensus of the 2-h PG for defining dysglycemic states during the OGTT. This article reviews the history of the OGTT and recent advances in its application, including the glucose challenge test and mathematical modeling for determining the shape of the glucose curve. Pitfalls of the FPG, 2-h PG during the OGTT, and HbA1c are considered as well. Finally, the associations between the 30-minute and 1-hour plasma glucose (1-h PG) levels derived from the OGTT and incidence of diabetes and its complications will be reviewed. The considerable evidence base supports modifying current screening and diagnostic recommendations with the use of the 1-h PG. Measurement of the 1-h PG level could increase the likelihood of identifying high-risk individuals when the pancreatic ß-cell function is substantially more intact with the added practical advantage of potentially replacing the conventional 2-h OGTT making it more acceptable in the clinical setting.

We present a case of recalcitrant post-surgical hypocalcemia caused by hypoparathyroidism further complicated by a chyle leak and treatment with octreotide. A 60-year-old man with 4 months of hoarseness, 10-poundweight loss, and right-sided neck mass presented with difficulty breathing for one week. Imaging showed a right laryngeal/ hypopharyngeal mass. Pathology results revealed an invasive squamous cell carcinoma. He underwent an extensive neck surgery, which included a total thyroidectomy with parathyroidectomy. Post-operative day 1, laboratory results revealed a corrected calcium of 7.6 mg/dL [8.0-10.2], magnesium of 1.2 mg/dL [ref 1.3-1.9], phosphorus of 5.3 mg/dL [2.7-4.5], parathyroid hormone of <6.3 pg/ mL, 25-hydroxyvitamin D level was 13.1 ng/mL. Patient denied symptoms of perioral numbness, tingling of extremites, or muscle cramping. Despite treatment with elemental calcium carbonate 12 grams daily, calcitriol 0.50 mcg daily, HCTZ 12.5 mg daily via PEG, his serum calcium levels remained low at 7.6 mg/dL. He required recurrent management with intravenous calcium gluconate. His severed throacic duct caused by a chyle leak was treated with octreotide 100 mg subcutaneously three times a day. Calcium carbonate was switched to calcium citrate 1900 mg three times a day to increase calcium absoprtion. The patient's chyle leak eventually resolved, octreotide was stopped, and his serum calcium further improved off of IV calcium. His calcium improved to 9.5 mg/dL and he was discharged with oral calcium citrate, calcitriol, and cholecalciferol. Extensive neck surgery caused hypoparathyroidism and a chyle leak, both contributing to hypocalcemia. Chyle contains calcium and fat soluble vitamin D. Octreotide decreases chyle flow and suppresses gastrointestinal hormones such as gastrin, decreasing the acid environment optimal for calcium carbonate absorption. The use of calcium citrate which is absorbed independently of gastric acidity, the resolution of the chyle leak, and the cessation of octreotide improved serum calcium levels. Post-surgical hypoparathyroidism can lead to hypocalcemia. This case is unique in that chyle leak and use of octreotide contributed to recalcitrant hypocalcemia

OBJECTIVE:Systemic inflammation contributes to cardiovascular disease in patients with type 2 diabetes, and elevated white blood cell (WBC) counts are an established risk factor. Our goal is to describe changes in WBCs and inflammatory markers after glycemic reductions in diabetes. RESEARCH DESIGN AND METHODS/METHODS:This study enrolled 63 subjects with poorly controlled diabetes, defined as hemoglobin A1c (HbA1c) ≥8% [64 mmol/mol]. Circulating granulocytes and mononuclear cells were separated by histopaque double-density protocol. Inflammatory markers from these isolated WBCs were assessed at baseline and after 3 months of medical management. RESULTS:After 3 months, significant glycemic reduction, defined as a decrease in HbA1c ≥ 1.5%, occurred in 42 subjects. Fasting plasma glucose decreased by 47% (165.6 mg/dL), and HbA1c decreased from 10.2 ± 1.8 to 6.8 ± 0.9. Glycemic reductions were associated with a 9.4% decrease in total WBC counts, 10.96% decrease in neutrophils, and 21.74% decrease in monocytes. The mRNA levels of inflammatory markers from granulocytes and mononuclear cells decreased, including receptor for advanced glycation endproducts; S100 calcium binding proteins A8, A9, A12; krüppel-like factor 5; and IL-1. Also, circulating levels of IL-1β and C-reactive protein decreased. Insulin dose was a mediator between HbA1c and both total WBC and neutrophil counts, but not changes in WBC inflammatory markers. In contrast, the 17 subjects without significant glycemic reductions showed no significant differences in their WBC counts and proteins of inflammatory genes. CONCLUSION/CONCLUSIONS:Significant glycemic reduction in subjects with poorly controlled diabetes led to reduced circulating WBC counts and inflammatory gene expression.