p8 was initially described as being overexpressed in acute pancreatitis and encoding a ubiquitous stress protein. Analysis of insulin sensitivity and glucose tolerance in p8-knockout and haplodeficient mice revealed counterintuitive results. Thus, we determined glycemic control of p8 in mice fed with standard (SD) and high-fat diet (HFD).

Linagliptin (TRADJENTA™) is a selective dipeptidyl peptidase-4 (DPP-4) inhibitor. DPP-4 inhibition attenuates insulin resistance and improves peripheral glucose utilization in humans. However, the effects of chronic DPP-4 inhibition on insulin sensitivity are not known. The effects of long-term treatment (3-4 weeks) with 3 mg/kg/day or 30 mg/kg/day linagliptin on insulin sensitivity and liver fat content were determined in diet-induced obese C57BL/6 mice. Chow-fed animals served as controls. DPP-4 activity was significantly inhibited (67-89%) by linagliptin (P<0.001). Following an oral glucose tolerance test, blood glucose concentrations (measured as area under the curve) were significantly suppressed after treatment with 3 mg/kg/day (-16.5% to -20.3%; P<0.01) or 30 mg/kg/day (-14.5% to -26.4%; P<0.05) linagliptin (both P<0.01). Liver fat content was significantly reduced by linagliptin in a dose-dependent manner (both doses P<0.001). Diet-induced obese mice treated for 4 weeks with 3 mg/kg/day or 30 mg/kg/day linagliptin had significantly improved glycated hemoglobin compared with vehicle (both P<0.001). Significant dose-dependent improvements in glucose disposal rates were observed during the steady state of the euglycemic-hyperinsulinemic clamp: 27.3 mg/kg/minute and 32.2 mg/kg/minute in the 3 mg/kg/day and 30 mg/kg/day linagliptin groups, respectively; compared with 20.9 mg/kg/minute with vehicle (P<0.001). Hepatic glucose production was significantly suppressed during the clamp: 4.7 mg/kg/minute and 2.1 mg/kg/minute in the 3 mg/kg/day and 30 mg/kg/day linagliptin groups, respectively; compared with 12.5 mg/kg/minute with vehicle (P<0.001). In addition, 30 mg/kg/day linagliptin treatment resulted in a significantly reduced number of macrophages infiltrating adipose tissue (P<0.05). Linagliptin treatment also decreased liver expression of PTP1B, SOCS3, SREBP1c, SCD-1 and FAS (P<0.05). Other tissues like muscle, heart and kidney were not significantly affected by the insulin sensitizing effect of linagliptin. Long-term linagliptin treatment reduced liver fat content in animals with diet-induced hepatic steatosis and insulin resistance, and may account for improved insulin sensitivity.

In obesity, elevated fat mass and ectopic fat accumulation are associated with changes in adipokine secretion, which may link obesity to inflammation and the development of insulin resistance. However, relationships among individual adipokines and between adipokines and parameters of obesity, glucose metabolism or inflammation are largely unknown. Serum concentrations of 20 adipokines were measured in 141 Caucasian obese men (n = 67) and women (n = 74) with a wide range of body weight, glycemia and insulin sensitivity. Unbiased, distance-based hierarchical cluster analyses were performed to recognize patterns among adipokines and their relationship with parameters of obesity, glucose metabolism, insulin sensitivity and inflammation. We identified two major adipokine clusters related to either (1) body fat mass and inflammation (leptin, ANGPTL3, DLL1, chemerin, Nampt, resistin) or insulin sensitivity/hyperglycemia, and lipid metabolism (vaspin, clusterin, glypican 4, progranulin, ANGPTL6, GPX3, RBP4, DLK1, SFRP5, BMP7, adiponectin, CTRP3 and 5, omentin). In addition, we found distinct adipokine clusters in subgroups of patients with or without type 2 diabetes (T2D). Logistic regression analyses revealed ANGPTL6, DLK1, Nampt and progranulin as strongest adipokine correlates of T2D in obese individuals. The panel of 20 adipokines predicted T2D compared to a combination of HbA1c, HOMA-IR and fasting plasma glucose with lower sensitivity (78% versus 91%) and specificity (76% versus 94%). Therefore, adipokine patterns may currently not be clinically useful for the diagnosis of metabolic diseases. Whether adipokine patterns are relevant for the predictive assessment of intervention outcomes needs to be further investigated.

Progranulin and C1q/TNF-related protein-3 (CTRP3) were recently discovered as novel adipokines which may link obesity with altered regulation of glucose metabolism, chronic inflammation and insulin resistance.

Acetyl coenzyme A carboxylase B gene (ACACB) single nucleotide polymorphism (SNP) rs2268388 is reproducibly associated with type 2 diabetes (T2DM)-associated nephropathy (DN). ACACB knock-out mice are also protected from obesity. This study assessed relationships between rs2268388, body mass index (BMI) and gene expression in multiple populations, with and without T2DM. Among subjects without T2DM, rs2268388 DN risk allele (T) associated with higher BMI in Pima Indian children (n = 2021; p-additive = 0.029) and African Americans (AAs) (n = 177; p-additive = 0.05), with a trend in European Americans (EAs) (n = 512; p-additive = 0.09), but not Germans (n = 858; p-additive = 0.765). Association with BMI was seen in a meta-analysis including all non-T2DM subjects (n = 3568; p-additive = 0.02). Among subjects with T2DM, rs2268388 was not associated with BMI in Japanese (n = 2912) or EAs (n = 1149); however, the T allele associated with higher BMI in the subset with BMI≥30 kg/m(2) (n = 568 EAs; p-additive = 0.049, n = 196 Japanese; p-additive = 0.049). Association with BMI was strengthened in a T2DM meta-analysis that included an additional 756 AAs (p-additive = 0.080) and 48 Hong Kong Chinese (p-additive = 0.81) with BMI≥30 kg/m(2) (n = 1575; p-additive = 0.0033). The effect of rs2268388 on gene expression revealed that the T risk allele associated with higher ACACB messenger levels in adipose tissue (41 EAs and 20 AAs with BMI>30 kg/m(2); p-additive = 0.018) and ACACB protein levels in the liver tissue (mixed model p-additive = 0.03, in 25 EA bariatric surgery patients with BMI>30 kg/m(2) for 75 exams). The T allele also associated with higher hepatic triglyceride levels. These data support a role for ACACB in obesity and potential roles for altered lipid metabolism in susceptibility to DN.

Intramyocellular triacylglycerol (IMTG) is utilized as metabolic fuel during exercise and is linked to insulin resistance, but the long-term effect of weight loss strategies on IMTG among participants with abdominal fat, remain unclear.

Leptin-deficient ob/ob mice are a model of type 2 diabetes induced peripheral neuropathy. Ob/ob mice exhibit obesity, insulin resistance, hyperglycaemia, and alterations of peripheral nerve fibres and endoneural microvessels. Here we test the hypothesis that cartilage oligomeric matrix protein (COMP)-Ang-1, a soluble and stabile form of Ang-1 which promotes angiogenesis and nerve growth, improves regeneration of nerve fibres and endoneural microvessels in ob/ob mice.