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We aimed to determine the extent of multiorgan fat accumulation and fibroinflammation in individuals living with type 2 diabetes. We deeply phenotyped individuals with type 2 diabetes (134 from secondary care, 69 from primary care) with multiorgan, quantitative, multiparametric MRI and compared with 134 matched control individuals without diabetes and 92 control individuals with normal weight. We examined the impact of diabetes duration, obesity status, and glycemic control. Ninety-three of the individuals with type 2 diabetes were reevaluated at 7 months (median). Multiorgan abnormalities were more common in individuals with type 2 diabetes (94%) than in age- and BMI-matched healthy individuals or healthy individuals with normal weight. We demonstrated a high burden of combined steatosis and fibroinflammation within the liver, pancreas, and kidneys (41%, 17%, and 10%) associated with visceral adiposity (73%) and poor vascular health (82%). Obesity was most closely associated with advanced liver disease, renal and visceral steatosis, and multiorgan abnormalities, while poor glycemic control was associated with pancreatic fibroinflammation. Pharmacological therapies with proven cardiorenal protection improved liver and vascular health unlike conventional glucose-lowering treatments, while weight loss or improved glycemic control reduced multiorgan adiposity (P ≤ 0.01). Quantitative imaging in people with type 2 diabetes highlights widespread organ abnormalities and may provide useful risk and treatment stratification. Article Highlights: Type 2 diabetes is a multisystem disease, but multiorgan imaging studies are lacking. The objective was to quantify organ abnormalities (steatosis and fibroinflammation) in type 2 diabetes using multiparametric MRI (mpMRI). In 126 of 134 individuals with type 2 diabetes, multiorgan abnormalities (steatosis and fibroinflammation) were detected with mpMRI, which persisted despite glucose-lowering therapy over 7 months. The therapeutic impact of new diabetes therapies on preventing or reversing end-organ damage can be measured by mpMRI. [ABSTRACT FROM AUTHOR]

Activation of AMP-activated protein kinase (AMPK) in animal muscle, by exercise, metformin, 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR) and adiponectin, increases glucose uptake. It is unknown whether AICAR stimulates muscle glucose uptake in people. We studied twenty one healthy men (26 ± 2 y, BMI 25 ± 1 kg⋅m[sup -2]; mean ± SEM) who underwent quadriceps muscle biopsies during 2-deoxyglucose (2DG) (10 mg⋅kg[sup -1]; 6 mg⋅kg[sup -1]⋅h[sup -1] and/or AICAR (10 mg⋅kg⋅h[sup -1]) infusions. Rates of muscle 2DG uptake were determined by measuring accumulation of total muscle 2DG (2DG and 2DG-6-phosphate, 2DG6P), which was linear over 9 h (R²= 0.89 ± 0.08; n=4). AICAR infusion doubled 2DG uptake (7.3 ± 2 to 15.6 ± 2 µmol⋅kg[sup -1]⋅kg[sup -1]⋅min [sup -1] P<0.01 Figure 1A) after 3 h. However, no detectable changes in AMPK-α[sub 1] and α[sub 2] activity, nor in AMPK phosphorylation, was observed after 20 min (n=4) or 3 h (n=10) of AICAR. In contrast, immediately after bicycle exercise AMPK phosphorylation was significantly increased (P<0.01, n=7). Extracellular-signal regulated kinase (ERK ½) phosphorylation significantly increased after a 3 h AICAR infusion(P<0.05 Figure 1B), but phosphorylation of β-acetylCoA carboxylase (β-ACC), glycogen synthase (GS), ribosomal protein S6 ($6), protein kinase B (PKB) or insulin receptor substrate levels (IRS1) were unchanged. Thus, AICAR stimulates 2DG uptake in healthy people, associated with increased ERK ½ phosphorylation, rather than AMPK activation. [ABSTRACT FROM AUTHOR]

Activation of AMP-activated protein kinase (AMPK) in rodent muscle by exercise, metformin, 5-aminoimidazole-4-carboxamide 1-beta-d-ribofuranoside (AICAR), and adiponectin increases glucose uptake. The aim of this study was to determine whether AICAR stimulates muscle glucose uptake in humans. We studied 29 healthy men (aged 26 +/- 8 years, BMI 25 +/- 4 kg/m(2) [mean +/- SD]). Rates of muscle 2-deoxyglucose (2DG) uptake were determined by measuring accumulation of total muscle 2DG (2DG and 2DG-6-phosphate) during a primed, continuous 2DG infusion. The effects of AICAR and exercise on muscle AMPK activity/phosphorylation and 2DG uptake were determined. Whole-body glucose disposal was compared before and during AICAR with the euglycemic-hyperinsulinemic clamp. Muscle 2DG uptake was linear over 9 h (R(2) = 0.88 +/- 0.09). After 3 h, 2DG uptake increased 2.1 +/- 0.8- and 4.7 +/- 1.7-fold in response to AICAR or bicycle exercise, respectively. AMPK alpha(1) and alpha(2) activity or AMPK phosphorylation was unchanged after 20 min or 3 h of AICAR, but AMPK phosphorylation significantly increased immediately and 3 h after bicycle exercise. AICAR significantly increased phosphorylation of extracellular signal-regulated kinase 1/2, but phosphorylation of beta-acetyl-CoA carboxylase, glycogen synthase, and protein kinase B or insulin receptor substrate-1 level was unchanged. Mean whole-body glucose disposal increased by 7% with AICAR from 9.3 +/- 0.6 to 10 +/- 0.6 mg x kg(-1) x min(-1) (P < 0.05). In healthy people, AICAR acutely stimulates muscle 2DG uptake with a minor effect on whole-body glucose disposal.

Insulin has been previously shown to regulate the expression of the hepatic glycogen-targeting subunit, G(L), of protein phosphatase 1 (PP1) and is believed to control the activity of the PP1-G(L) complex by modulation of the level of phosphorylase a, which allosterically inhibits the activity of PP1-G(L). These mechanisms contribute to the ability of insulin to increase hepatic glycogen synthesis. Human G(L) shows >88% amino acid identity to its rat and mouse homologs, with complete conservation of the phosphorylase a binding site. G(L) is highly expressed in the liver and present at appreciable levels in heart tissue of all three species. Surprisingly, G(L) is highly expressed in human skeletal muscle while only being detected at very low levels in rat, mouse, and rabbit skeletal muscle. The amino acid sequence of G(L) predicted from the cDNA is identical in human liver and skeletal muscle and encoded by a gene on chromosome 8 at p23.1. The species-specific difference in the level of expression of G(L) mRNA and protein in skeletal muscle has important implications for understanding the mechanisms by which insulin regulates glycogen synthesis in human skeletal muscle and for questions regarding whether rodents are appropriate models for this purpose.