Citations

Basal insulin supplementation has been used as a therapy for patients with non-insulin-dependent diabetes mellitus (NIDDM) who require insulin. To determine whether basal insulin supplementation in addition to lowering postabsorptive plasma glucose concentration also improves the postprandial pattern of glucose disposition, glucose metabolism after ingestion of a solid mixed meal was assessed in obese patients with NIDDM before and after treatment with ultralente and compared with glucose metabolism observed in nondiabetic subjects. Splanchnic uptake of ingested glucose clearance was assessed by including [2-3H]glucose (a tracer that only minimally cycles through glycogen) in a solid mixed meal. Postprandial gluconeogenesis was estimated by measuring the rate of incorporation of carbon dioxide into glucose. Net glucose and lipid oxidation were measured by indirect calorimetry. Both splanchnic uptake of ingested glucose (27 ± 1 vs. 14 ± 2 g) and postprandial hepatic glucose release (51 ± 5 vs. 24 ± 3 g) were greater (P < .001) in diabetic than in nondiabetic subjects. Although the percentage of postprandial hepatic glucose release accounted for by glucose synthesis from bicarbonate was similar in the two groups (25 ± 2 vs. 35 ± 5%), the absolute rate was greater in the diabetic patients (13 ± 1 vs. 8 ± 1 g; P < .05). Postprandial glucose oxidation and glucose disposal (measured either isotopically or by the forearm-catheterization technique) were similar in both groups. However, total lipid oxidation was increased in the diabetic patients. (P < .05). Two weeks of basal insulin supplementation lowered fasting glucose concentrations (from 219 ± 22 to 144 ± 21 mg/dl; P < .01) and integrated postprandial glycemic response (from 814 ± 68 to 621 ± 72 min · mg· ml−1) but not to normal. Although circulating insulin concentrations were two- to threefold greater (P < .02) after 3 mo of basal insulin supplementation, the postprandial pattern of glucose metabolism remained essentially the same. Basal insulin supplementation decreased (P < .05) both splanchnic uptake of ingested glucose and hepatic glucose release. The addition of a preprandial injection of soluble insulin to basal insulin supplementation further suppressed (P < .05) postprandial hepatic glucose release, thereby further improving postprandial glucose tolerance. These studies indicate that initial splanchnic glucose clearance, hepatic glucose release, and new glucose synthesis, as well as extrahepatic substrate metabolism, are altered in NIDDM after ingestion of a mixed meal. Basal insulin supplementation improves but does not normalize postprandial glucose metabolism.

Recent studies indicate that hydrogen-labeled glucose tracers underestimate glucose turnover in humans under conditions of high flux. The cause of this underestimation is unknown. To determine whether the error is time-, pool-, model-, or insulin-dependent, glucose turnover was measured simultaneously with [6-3H]-, [6,6-2H2]-, and [6-14C]glucose during a 7-h infusion of either insulin (1 mU · kg−1 · min−1) or saline. During the insulin infusion, steady-state glucose turnover measured with both [6-3H]glucose (8.0 ± 0.5 mg · kg−1 · min−1) and [6,6-2H2]glucose (7.6 ± 0.5 mg kg−1 min−1) was lower (P < .01) than either the glucose infusion rate required to maintain euglycemia (9.8 ± 0.6 mg · kg−1 · min−1) or glucose turnover determined with [6-14 C]glucose and corrected for Cori cycle activity (9.8 ± 0.7 mg · kg−1 · min1). Consequently “negative” glucose production rates (P <.01) were obtained with either [6-3 H]- or [6,6-2 H2]-but not [6-14 C]glucose. The difference between turnover estimated with [6-3 H]glucose and actual glucose disposal (or 14C glucose flux) did not decrease with time and was not dependent on duration of isotope infusion. During saline infusion, estimates of glucose turnover were similar regardless of the glucose tracer used. High-performance liquid chromatography of the radioactive glucose tracer and plasma revealed the presence of a tritiated nonglucose contaminant. Although the contaminant represented only 1.5% of the radioactivity in the [6-3H]glucose infusate, its clearance was 10-fold less (P <.001) than that of [6-3H]glucose. This resulted in accumulation in plasma, with the contaminant accounting for 16.6 ± 2.09 and 10.8 ± 0.9% of what customarily is assumed to be plasma glucose radioactivity during the insulin or saline infusion, respectively (P < .01). When corrected for the presence of the contaminant, glucose turnover determined with [6-3H]glucose during insulin infusion (9.5 ± 0.6 mg · kg−1 · min−1) no longer differed from either the glucose infusion rate or that determined with [6-14C]glucose. Therefore, the underestimation of glucose turnover during insulin infusion and negative glucose production rates observed with traditional methods to analyze plasma radioactivity and commercially available tracers is the result of an artifactual increase in [6-3H]glucose specific activity. The etiology of the underestimation of glucose turnover with [6,6-2H2]glucose remains to be determined.

SummaryMutations of the SCN1A subunit of the sodium channel is a cause of genetic epilepsy with febrile seizures plus (GEFS+) in multiplex families and accounts for 70–80% of Dravet syndrome (DS). DS cases without SCN1A mutation inherited have predicted SCN9A susceptibility variants, which may contribute to complex inheritance for these unexplained cases of DS. Compared with controls, DS cases were significantly enriched for rare SCN9A genetic variants. None of the multiplex febrile seizure or GEFS+ families could be explained by highly penetrant SCN9A mutations.

Genetic College Many genomic elements in humans are associated with behavior, including educational attainment. In a genome-wide association study including more than 100,000 samples, Rietveld et al. (p. 1467 , published online 30 May; see the Perspective by Flint and Munafò ) looked for genes related to educational attainment in Caucasians. Small genetic effects at three loci appeared to impact educational attainment.

The left ventricle (LV) pumps oxygenated blood from the lungs to the rest of the body through systemic circulation. The efficiency of such a pumping function is dependent on blood flow within the LV chamber. It is therefore crucial to accurately characterize LV hemodynamics. Improved understanding of LV hemodynamics is expected to provide important clinical diagnostic and prognostic information. We review the recent advances in numerical and experimental methods for characterizing LV flows and focus on analysis of intraventricular flow fields by echocardiographic particle image velocimetry (echo-PIV), due to its potential for broad and practical utility. Future research directions to advance patient-specific LV simulations include development of methods capable of resolving heart valves, higher temporal resolution, automated generation of three-dimensional (3D) geometry, and incorporating actual flow measurements into the numerical solution of the 3D cardiovascular fluid dynamics.

Pharmacokinetics of drugs may differ between small and large mammals (including humans); therefore, drug testing in animal models must be carefully designed. Sprague–Dawley rats were used in cardiac experiments, during which the lopinavir concentration in serum had to match human therapeutic levels (4–10 μg/mL). Lopinavir was administered as a co-formulated drug of lopinavir and ritonavir. It was found that after a single administration of a standard human peroral dose (lopinavir 13.3 mg/kg of body weight), the serum concentration of lopinavir was only one-tenth of the target level. It remained below the minimum target level even after 10-fold the standard dose was administered. After initial pilot tests, a dose escalation study was conducted with oral doses 10- and 15-fold the standard clinical dose of lopinavir (i.e. 133 and 200 mg/kg, respectively). A second administration 2 h later effectively increased and maintained higher concentrations during the experimental ischaemia and reperfusion periods. A dose-dependent increase in serum concentration of the drug was observed. Thus, the target therapeutic serum level of lopinavir in the rats was achieved by administrating 10- to 15-fold the standard human dose twice, separated by a 2 h interval.

Aberrant connectivity is implicated in many neurological and psychiatric disorders, including Alzheimer’s disease and schizophrenia. However, other than a few disease-associated candidate genes, we know little about the degree to which genetics play a role in the brain networks; we know even less about specific genes that influence brain connections. Twin and family-based studies can generate estimates of overall genetic influences on a trait, but genome-wide association scans (GWASs) can screen the genome for specific variants influencing the brain or risk for disease. To identify the heritability of various brain connections, we scanned healthy young adult twins with high-field, high-angular resolution diffusion MRI. We adapted GWASs to screen the brain’s connectivity pattern, allowing us to discover genetic variants that affect the human brain’s wiring. The association of connectivity with the SPON1 variant at rs2618516 on chromosome 11 (11p15.2) reached connectome-wide, genome-wide significance after stringent statistical corrections were enforced, and it was replicated in an independent subsample. rs2618516 was shown to affect brain structure in an elderly population with varying degrees of dementia. Older people who carried the connectivity variant had significantly milder clinical dementia scores and lower risk of Alzheimer’s disease. As a posthoc analysis, we conducted GWASs on several organizational and topological network measures derived from the matrices to discover variants in and around genes associated with autism ( MACROD2 ), development ( NEDD4 ), and mental retardation ( UBE2A ) significantly associated with connectivity. Connectome-wide, genome-wide screening offers substantial promise to discover genes affecting brain connectivity and risk for brain diseases.