In rodent models, obesity and hyperglycemia alter cerebral glucose metabolism and glucose transport into the brain, resulting in disordered cerebral function as well as inappropriate responses to homeostatic and hedonic inputs. Whether similar findings are seen in the human brain remains unclear. In this study, 25 participants (9 healthy participants; 10 obese nondiabetic participants; and 6 poorly controlled, insulin- and metformin-treated type 2 diabetes mellitus (T2DM) participants) underwent 1H magnetic resonance spectroscopy scanning in the occipital lobe to measure the change in intracerebral glucose levels during a 2-hour hyperglycemic clamp (glucose ~220 mg/dl). The change in intracerebral glucose was significantly different across groups after controlling for age and sex, despite similar plasma glucose levels at baseline and during hyperglycemia. Compared with lean participants, brain glucose increments were lower in participants with obesity and T2DM. Furthermore, the change in brain glucose correlated inversely with plasma free fatty acid (FFA) levels during hyperglycemia. These data suggest that obesity and poorly controlled T2DM progressively diminish brain glucose responses to hyperglycemia, which has important implications for understanding not only the altered feeding behavior, but also the adverse neurocognitive consequences associated with obesity and T2DM.

The impact of glycemic variability on brain glucose transport kinetics among individuals with type 1 diabetes mellitus (T1DM) remains unclear. Fourteen individuals with T1DM (age 35 ± 4 years; BMI 26.0 ± 1.4 kg/m2; HbA1c 7.6 ± 0.3) and nine healthy control participants (age 32 ± 4; BMI 23.1 ± 0.8; HbA1c 5.0 ± 0.1) wore a continuous glucose monitor (Dexcom) to measure hypoglycemia, hyperglycemia, and glycemic variability for 5 days followed by 1H MRS scanning in the occipital lobe to measure the change in intracerebral glucose levels during a 2-h glucose clamp (target glucose concentration 220 mg/dL). Hyperglycemic clamps were also performed in a rat model of T1DM to assess regional differences in brain glucose transport and metabolism. Despite a similar change in plasma glucose levels during the hyperglycemic clamp, individuals with T1DM had significantly smaller increments in intracerebral glucose levels (P = 0.0002). Moreover, among individuals with T1DM, the change in brain glucose correlated positively with the lability index (r = 0.67, P = 0.006). Consistent with findings in humans, streptozotocin-treated rats had lower brain glucose levels in the cortex, hippocampus, and striatum compared with control rats. These findings that glycemic variability is associated with brain glucose levels highlight the need for future studies to investigate the impact of glycemic variability on brain glucose kinetics.

ContextMost heritable causes of low bone mass in children occur due to mutations affecting type 1 collagen. We describe two related patients with low bone mass and fracture without mutations in the type 1 collagen genes.Case descriptionWe describe the index case of a 10-year-old girl with low-impact fractures in childhood and her 59-year-old father with traumatic fractures in adulthood, both with low bone mineral density. They were found to have the same heterozygous missense mutation in the WNT1 gene (p.Gly222Arg), occurring in a highly conserved WNT motif in close proximity to the Frizzled binding site.ConclusionsThe WNT-ligand WNT1, signaling through the canonical WNT-β­catenin pathway, plays a critical role in skeletal development, adult skeletal homeostasis, and bone remodeling. Biallelic mutations have been described and are associated with moderate to severe osteogenesis imperfecta, in some cases with extra-skeletal manifestations. Patients with monoallelic mutations, as in our case, seem to present with low bone mineral density and less severe disease. The phenotypic difference between biallelic and monoallelic mutations highlights that the aberrant protein in monoallelic mutations may exert a dominant negative effect on the wild type protein as heterozygous carriers in families with biallelic disease are usually asymptomatic. With better understanding of disorders associated with WNT1 mutations, therapies targeting this signaling pathway may offer therapeutic benefit.

Poor glycemic control is associated with central nervous system complications. We have previously shown that compared to healthy controls, individuals with uncontrolled T2DM have a blunted rise in brain glucose levels measured by 1H magnetic resonance spectroscopy (MRS). In this study, we investigate whether reduction in HbA1C improves intracerebral glucose levels. Six T2DM subjects with poor glycemic control were recruited (4F, age 46.0 ± 8.8 yrs, BMI 34.2 ± 4.1 kg/m2, HgbA1c 9.6 ± 1.1%) to participate in 1HMRS scanning at 4 Tesla during a hyperglycemic clamp (∼220 mg/dl) before and after a 12-week intervention to improve glycemic control through use of continuous glucose monitoring, intensification of diabetes regimen, and frequent visits with an endocrinologist and nutritionist. Following the intervention, HbA1c decreased by 2.1%±1.5 (P=0.02) with minimal BMI changes (P=0.10). Using a hierarchical linear regression model to compare glucose time courses during the clamp pre and post intervention, brain glucose levels were modestly and significantly higher during the clamp after the intervention (P=0.02) despite no differences in plasma glucose levels during the clamp (P=0.45). These findings suggest that brain glucose levels increase after improvement of glycemic control and provide evidence that reducing HbA1C may improve brain glucose transport and/or metabolism. Disclosure E. Sanchez Rangel: None. F. Gunawan: None. L. Jiang: None. M. Savoye: None. F. Dai: None. D.L. Rothman: None. G.F. Mason: None. J.J. Hwang: Research Support; Self; General Electric. Funding National Institutes of Health (DK109284)

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