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OBJECTIVE-Long-standing type 1 diabetes is associated with deficits on neurocognitive testing that suggest central white matter dysfunction. This study investigated whether diffusion tensor imaging (DTI), a type of magnetic resonance imaging that measures white matter integrity quantitatively, could identify white matter microstructural deficits in patients with longstanding type 1 diabetes and whether these differences would be associated with deficits found by neurocognitive tests.RESEARCH DESIGN AND METHODS-Twenty-five subjects with type 1 diabetes for at least 15 years and 25 age-and sex-matched control subjects completed DTI on a 3.0 Tesla scanner and a battery of neurocognitive tests. Fractional anisotropy was calculated for the major white matter tracts of the brain.RESULTS-Diabetic subjects had significantly lower mean fractional anisotropy than control subjects in the posterior corona radiata and the optic radiation (P Ͻ 0.002). In type 1 diabetic subjects, reduced fractional anisotropy correlated with poorer performance on the copy portion of the Rey-Osterreith Complex Figure Drawing Test and the Grooved Peg Board Test, both of which are believed to assess white matter function. Reduced fractional anisotropy also correlated with duration of diabetes and increased A1C. A history of severe hypoglycemia did not correlate with fractional anisotropy.CONCLUSIONS-DTI can detect white matter microstructural deficits in subjects with long-standing type 1 diabetes. These deficits correlate with poorer performance on selected neurocognitive tests of white matter function. Diabetes 57:3083-3089, 2008

OBJECTIVEWe tested the hypotheses that human brain glycogen is mobilized during hypoglycemia and its content increases above normal levels (“supercompensates”) after hypoglycemia.RESEARCH DESIGN AND METHODSWe utilized in vivo 13C nuclear magnetic resonance spectroscopy in conjunction with intravenous infusions of [13C]glucose in healthy volunteers to measure brain glycogen metabolism during and after euglycemic and hypoglycemic clamps.RESULTSAfter an overnight intravenous infusion of 99% enriched [1-13C]glucose to prelabel glycogen, the rate of label wash-out from [1-13C]glycogen was higher (0.12 ± 0.05 vs. 0.03 ± 0.06 μmol · g−1 · h−1, means ± SD, P < 0.02, n = 5) during a 2-h hyperinsulinemic-hypoglycemic clamp (glucose concentration 57.2 ± 9.7 mg/dl) than during a hyperinsulinemic-euglycemic clamp (95.3 ± 3.3 mg/dl), indicating mobilization of glucose units from glycogen during moderate hypoglycemia. Five additional healthy volunteers received intravenous 25–50% enriched [1-13C]glucose over 22–54 h after undergoing hyperinsulinemic-euglycemic (glucose concentration 92.4 ± 2.3 mg/dl) and hyperinsulinemic-hypoglycemic (52.9 ± 4.8 mg/dl) clamps separated by at least 1 month. Levels of newly synthesized glycogen measured from 4 to 80 h were higher after hypoglycemia than after euglycemia (P ≤ 0.01 for each subject), indicating increased brain glycogen synthesis after moderate hypoglycemia.CONCLUSIONSThese data indicate that brain glycogen supports energy metabolism when glucose supply from the blood is inadequate and that its levels rebound to levels higher than normal after a single episode of moderate hypoglycemia in humans.

OBJECTIVEPrevious studies have observed disruptions in brain white and gray matter structure in individuals with type 1 diabetes, and these structural differences have been associated with neurocognitive testing deficiencies. This study investigated the relationship between cerebral cortical thickness reductions and white matter microstructural integrity loss in a group of patients with type 1 diabetes and in healthy control subjects using diffusion tensor imaging (DTI).RESEARCH DESIGN AND METHODSTwenty-five subjects with type 1 diabetes for at least 15 years and 25 age- and sex-matched control subjects underwent structural T1 and proton-density and DTI on a 3.0 Tesla scanner. Fractional anisotropy measurements were made on major cerebral white matter tracts, and DTI tractography was performed to identify cortical regions with high connectivity to these tracts.RESULTSPosterior white matter tracts with reduced fractional anisotropy (optic radiations, posterior corona radiata, and the splenium region of the corpus callosum) were found to have high connectivity with a number of posterior cortical regions, including the cuneus, precuneus, fusiform, and posterior parietal cortical regions. A significant reduction in cortical thickness in the diabetic group was observed in the regions with high connectivity to the optic radiations and posterior corona radiata tracts (P < 0.05).CONCLUSIONSThe direct relationship between white and gray matter structural pathology has not been previously demonstrated in subjects with long-standing type 1 diabetes. The relationship between posterior white matter microstructural integrity disruption and lower cortical thickness demonstrated using a novel DTI connectivity technique suggests a common or interrelated pathophysiological mechanism in type 1 diabetes.

Brief myocardial ischemia (ISC) is known to attenuate purine metabolite accumulation in the interstitial fluid (ISF) during subsequent ISC. We determined how this attenuated purine accumulation was altered by 1) extended reperfusion (REP) and 2) multiple cycles of brief ISC. Microdialysis probes were used to assess ISF levels of the purine metabolites adenosine, inosine, and hypoxanthine in anesthetized rabbits. In one series of experiments, two 10 min periods of regional ISC were separated by 10 (n = 6), 60 (n = 6), or 180 (n = 6) min of REP. In the 10, 60, and 180 min REP groups the increase in ISF purine metabolites during the second ISC was 47%, 55%, and 53% of that seen during the first ISC, respectively. In a second series of experiments, hearts were exposed to 120 min of ISC with (n = 6) or without (n = 6) five preceding cycles of transient ISC (10 min ISC; 10 min of REP). The increase in ISF purine metabolites during the multiple cycles of ISC was progressively attenuated, and there was a delay but eventual increase in ISF purine metabolites during the 120 min ISC. These data demonstrate that attenuated purine metabolite accumulation 1) is progressively greater with multiple cycles of brief ISC, 2) has a memory time of at least 180 min, and 3) is not due to high energy phosphate depletion.