Objective: Although clinical hypothyroidism (HO) is associated with insulin resistance, there is no information on insulin action in subclinical hypothyroidism (SHO). Design and methods: To investigate this, we assessed the sensitivity of glucose metabolism to insulin both in vivo (by an oral glucose tolerance test) and in vitro (by measuring insulin-stimulated rates of glucose transport in isolated monocytes with flow cytometry) in 21 euthyroid subjects (EU), 12 patients with HO, and 13 patients with SHO. Results: All three groups had comparable plasma glucose levels, with the HO and SHO having higher plasma insulin than the EU (P!0.05). Homeostasis model assessment index was increased in HO (1.97G0.22) and SHO (1.99G0.13) versus EU (1.27G0.16, P!0.05), while Matsuda index was decreased in HO (3.89G0.36) and SHO (4.26G0.48) versus EU (7.76G0.87, P!0.001), suggesting insulin resistance in both fasting and post-glucose state. At 100 mU/ml insulin: i) GLUT4 levels on the monocyte plasma membrane were decreased in both HO (215G19 mean fluorescence intensity, MFI) and SHO (218G24 MFI) versus EU (270G25 MFI, PZ0.03 and 0.04 respectively), and ii) glucose transport rates in monocytes from HO (481G30 MFI) and SHO (462G19 MFI) were decreased versus EU (571G15 MFI, PZ0.04 and 0.004 respectively). Conclusions: In patients with HO and SHO: i) insulin resistance was comparable; ii) insulin-stimulated rates of glucose transport in isolated monocytes were decreased due to impaired translocation of GLUT4 glucose transporters on the plasma membrane; iii) these findings could justify the increased risk for insulin resistance-associated disorders, such as cardiovascular disease, observed in patients with HO or SHO.

Many patients with hyperglycemic crises present with combined features of diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS). The implications of concomitant acidosis and hyperosmolality are not well known. We investigated hospital outcomes in patients with isolated or combined hyperglycemic crises. RESEARCH DESIGN AND METHODSWe analyzed admissions data listing DKA or HHS at two academic hospitals. We determined 1) the frequency distributions of HHS, DKA, and combined DKA-HHS (DKA criteria plus elevated effective osmolality); 2) the relationship of markers of severity of illness and clinical comorbidities with 30-day all-cause mortality; and 3) the relationship of hospital complications associated with insulin therapy (hypoglycemia and hypokalemia) with mortality. RESULTSThere were 1,211 patients who had a first admission with confirmed hyperglycemic crises criteria, 465 (38%) who had isolated DKA, 421 (35%) who had isolated HHS, and 325 (27%) who had combined features of DKA-HHS. After adjustment for age, sex, BMI, race, and Charlson Comorbidity Index score, subjects with combined DKA-HHS had higher in-hospital mortality compared with subjects with isolated hyperglycemic crises (adjusted odds ratio [aOR] 2.7; 95% CI 1.4, 4.9; P 5 0.0019). In all groups, hypoglycemia (<40 mg/dL) during treatment was associated with a 4.8fold increase in mortality (aOR 4.8; 95% CI 1.4, 16.8). Hypokalemia £3.5 mEq/L was frequent (55%). Severe hypokalemia (£2.5 mEq/L) was associated with increased inpatient mortality (aOR 4.9; 95% CI 1.3, 18.8; P 5 0.02). CONCLUSIONSCombined DKA-HHS is associated with higher mortality compared with isolated DKA or HHS. Severe hypokalemia and severe hypoglycemia are associated with higher hospital mortality in patients with hyperglycemic crises.

Objective: Although clinical hyperthyroidism (HR) is associated with insulin resistance, the information on insulin action in subclinical hyperthyroidism (SHR) is limited. Design and methods: To investigate this, we assessed the sensitivity of glucose metabolism to insulin in vivo (by an oral glucose tolerance test) and in vitro (by measuring insulin-stimulated rates of glucose transport in isolated monocytes) in 12 euthyroid subjects (EU), 16 patients with HR, and 10 patients with SHR. Results: HR and SHR patients displayed higher postprandial glucose levels (area under the curve, AUC 0-300 32 190G1067 and 31 497G716 mg/dl min respectively) versus EU (27 119 G1156 mg/dl min, P!0.05). HR but not SHR patients displayed higher postprandial insulin levels (AUC 0-300 11 020G985 and 9565G904 mU/l min respectively) compared with EU subjects (AUC 0-300 7588G743 mU/l min, P!0.05). Homeostasis model assessment index was increased in HR and SHR patients (2.81G0.3 and 2.43G0.38 respectively) compared with EU subjects (1.27 G0.16, P!0.05), while Matsuda and Belfiore indices were decreased in HR (4.21G0.41 and 0.77G0.05 respectively, P!0.001) and SHR patients (4.47G0.33 and 0.85G0.05 respectively, P!0.05 versus EU (7.76G0.87 and 1 respectively). At 100 mU/ml insulin, i) GLUT3 levels on the monocyte plasma membrane were increased in HR (468.8G7 mean fluorescence intensity (MFI)) and SHR patients (522.2G25 MFI) compared with EU subjects (407G18 MFI, P!0.01 and P!0.05 respectively), ii) glucose transport rates in monocytes (increases from baseline) were decreased in HR patients (37.8G5%) versus EU subjects (61.26G10%, P!0.05). Conclusions: Insulin-stimulated glucose transport in isolated monocytes of patients with HR was decreased compared with EU subjects. Insulin resistance was comparable in patients with both HR and SHR.

Objective: In hyperthyroidism, tissue glucose disposal is increased to adapt to high energy demand. Our aim was to examine the regulation of glucose transporter (GLUT) isoforms by IGF-I in monocytes from patients with hyperthyroidism. Design and methods: Blood (20 ml) was drawn from 21 healthy and 10 hyperthyroid subjects. The abundance of GLUT isoforms on the monocyte plasma membrane was determined in the absence and presence of IGF-I (0.07, 0.14, and 0.7 nM) using flow cytometry. Anti-CD14-phycoerythrin monocional antibody was used for monocyte gating. GLUT isoforms were determined after staining the cells with specific antisera to GLUT3 and GLUT4. Results: In monocytes from the euthyroid subjects, IGF-I increased the abundance of GLUT3 and GLUT4 on the monocyte surface by 25 and 21% respectively (P!0.0005 with repeated measures ANOVA). Hyperthyroidism increased the basal monocyte surface GLUT3 and GLUT4; in these cells, IGF-I had a marginal but highly significant effect (PZ0.003, with repeated measures ANOVA) on GLUT3 (11%) and GLUT4 (10%) translocation on the plasma membrane. Conclusions: In hyperthyroidism: 1) basal abundance of GLUT3 and GLUT4 on the plasma membrane is increased and 2) the sensitivity of the recruitment of GLUT3 and GLUT4 transporters on the plasma membrane in response to IGF-I is increased. These findings may contribute to the understanding of the mechanism by which hyperthyroidism increases glucose disposal in peripheral tissues.

IntroductionThere is limited evidence to guide management in patients with end-stage renal disease (ESRD) on chronic hemodialysis admitted with diabetes ketoacidosis. Thus, we investigated the clinical characteristics and outcomes of patients with ESRD admitted with diabetic ketoacidosis (DKA).MethodsIn this observational study, we used International Classification of Diseases Ninth/Tenth Revision codes to identify adult (aged 18–80 years) patients admitted to Emory University Hospitals between 1 January 2006 and 31 December 2016. DKA and ESRD diagnoses were confirmed by reviewing medical records and by admission laboratory results.ResultsAmong 307 patients with DKA meeting the inclusion and exclusion criteria, 22.1% (n: 68) had ESRD on hemodialysis and 77.9% (n: 239) had preserved renal function (estimated glomerular filtration rate >60 mL/min/1.73 m2). Compared with patients with preserved renal function, the admission blood glucose was higher (804.5±362.6 mg/dL vs 472.5±137.7 mg/dL) and the mean hemoglobin A1c was lower (9.6%±2.1 vs 12.0%±2.5) in patients with DKA and ESRD, both p<0.001. The rates of hypoglycemia <70 mg/dL (34% vs 14%, p=0.002) and <54 mg/dL (13% vs 5%, p=0.04) were higher in the ESRD group. During hospitalization, more patients with ESRD develop volume overload (28% vs 3%, p<0.001) and require mechanical ventilation (24% vs 3%, p=<0.001). There were no differences in hospital mortality (3% vs 0%, p=0.21), but length of stay (median 7.0 vs 3.0 days, p<0.001) was longer in the ESRD cohort. After adjusting for multiple covariates, patients with DKA and ESRD have higher odds of hypoglycemia (OR 3.3, 95% CI 1.51 to 7.21, p=0.003) and volume overload (OR 4.22, 95% CI 1.37 to 13.05, p=0.01) compared with patients with DKA with preserved renal function.ConclusionsPatients with DKA and ESRD on chronic hemodialysis had worse clinical outcomes including higher rates of hypoglycemia, volume overload, need for mechanical ventilation and longer length of stay, compared with patients with preserved kidney function.