Type 2 diabetes (T2D) is associated with an accelerated episodic memory decline, but the underlying pathophysiological mechanisms are not well understood. Hallmarks of T2D comprise impairment of insulin secretion and insulin sensitivity. Insulin signaling modulates cerebral neurotransmitter activity, including the excitatory glutamate and inhibitory gamma‐aminobutyric acid (GABA) systems. Here we tested the hypothesis that the glutamate and GABA systems are altered in T2D patients and this relates to memory decline and insulin resistance. Using 1H‐magnetic resonance spectroscopy (MRS), we examined glutamate and GABA concentrations in episodic memory relevant brain regions (medial prefrontal cortex and precuneus) of T2D patients and matched controls. Insulin sensitivity was measured by hyperinsulinemic‐euglycemic clamps and memory performance was assessed using a face‐profession associations test. T2D patients exhibited peripheral insulin resistance and had a decreased memory for face‐profession associations as well as elevated GABA concentration in the medial prefrontal cortex but not precuneus. In addition, medial prefrontal cortex GABA concentration was negatively associated with memory performance suggesting that abnormal GABA levels in the medial prefrontal cortex are linked to the episodic memory decline that occurs in T2D patients.

Context Vitamin B12 and folate deficiency are not only linked to hematological, neurological, and cardiovascular diseases, but are also associated with insulin resistance. Metformin can decrease vitamin B12 and folate concentrations. Objective To examine (1) effects of short-term metformin treatment on serum holotranscobalamin (holoTC) and folate and (2) their association with insulin sensitivity in recent-onset type 2 diabetes. Design This cross-sectional analysis comprised patients (known disease duration <12 months) on metformin monotherapy (MET, n = 123, 81 males, 53 ± 12 years) or nonpharmacological treatment (NPT, n = 126, 77 males, 54 ± 11 years) of the German Diabetes Study. Main Outcome Measures HoloTC (enzyme-linked immunosorbent assay), cobalamin, and folate (electrochemiluminescence); beta-cell function and whole-body insulin sensitivity, measured during fasting (HOMA-B, HOMA-IR) and intravenous glucose tolerance tests combined with hyperinsulinemic–euglycemic clamp tests. Results HoloTC (105.4 [82.4, 128.3] vs 97 [79.7, 121.9] pmol/L) and folate concentrations (13.4 [9.3, 19.3] vs 12.7 [9.3, 22.0] nmol/L) were similar in both groups. Overall, holoTC was not associated with fasting or glucose-stimulated beta-cell function and insulin-stimulated glucose disposal. Cobalamin measurements yielded similar results in representative subgroups. In NPT but not MET, folate levels were inversely correlated with HOMA-IR (r = –0.239, P = .007). Folate levels did not relate to insulin sensitivity or insulin secretion in the whole cohort and in each group separately after adjustment for age, body mass index, and sex. Conclusions Metformin does not affect circulating holoTC and folate concentrations in recent-onset type 2 diabetes, rendering monitoring of vitamin B12 and folate dispensable, at least during the first 6 months after diagnosis or initiation of metformin.

High intramyocellular lipid (IMCL) content associates negatively with insulin sensitivity (IS) in insulin resistant, but not in endurance-trained humans. It has been hypothesized that different cellular distribution of bioactive lipids such as diacylglycerols (DAG) and ceramides (CER) could interfere with insulin action and underlie this “athlete’s paradox.” We examined endurance-trained athletes (ATH; n=9) and sedentary individuals (SED; n=12) with comparable total IMCL, as measured by 1H-magnetic resonance spectroscopy, who underwent spiroergometry and hyperinsulinemic-euglycemic clamps to assess maximal oxidative capacity and IS, respectively. In skeletal muscle biopsies, translocation of protein kinase C (PKC) θ and ε were determined by Western blotting and concentrations of DAG and CER were measured using targeted LC-tandem mass spectrometry upon separating fractions of cellular membranes, lipid droplets and cytosol by ultracentrifugation. Maximal oxidative capacity and IS were 46% and 47% higher in ATH than in SED (both p<0.01), respectively. The membrane:cytosol ratio of PKCθ, which reflects PKCθ activity, was 62% lower in ATH consistent with their increased IS (p<0.01), while there was no group difference for PKCε. Total and membrane DAG (40% and 48%, both p<0.01) as well as membrane CER (15%, p<0.05) were higher in ATH while the respective concentrations in lipid droplets and cytosol did not differ. In SED, IS correlated inversely with all stereoselective subspecies of lipid-droplet DAG. On the other hand, cytosolic sn-1,2 (C16:0-C18:2) and sn-1,3 (C18:1-C18:0) DAG correlated positively with IS in ATH. In conclusion, higher IS in endurance-trained ATH can be explained by lower muscle PKCθ activation, which may be due to differences in the stereoselectivity and/or subcompartmentation of cellular DAG between ATH and insulin resistant SED. Disclosure D. Pesta: None. E. Anadol-Schmitz: None. S. Gancheva: None. D.F. Markgraf: None. O.P. Zaharia: None. H. Katsuyama: None. Y. Kupriyanova: None. J. Hwang: None. D. Zhang: None. G.I. Shulman: Advisory Panel; Self; AstraZeneca, Janssen Research & Development, Merck & Co., Inc., Novo Nordisk Inc.. Research Support; Self; Gilead Sciences, Inc. M. Roden: Speaker's Bureau; Self; Boehringer Ingelheim GmbH. Research Support; Self; Boehringer Ingelheim GmbH. Consultant; Self; Poxel SA. Research Support; Self; Danone Nutricia Early Life Nutrition, GlaxoSmithKline plc., Nutricia Advanced Medical Nutrition, Sanofi.