Adipocyte-specific protein tyrosine phosphatase 1B deletion increases lipogenesis, adipocyte cell size and is a minor regulator of glucose homeostasis

Peer reviewedPublisher PD

Community based yoga classes for type 2 diabetes: an exploratory randomised controlled trial

Abstract Background Yoga is a popular therapy for diabetes but its efficacy is contested. The aim of this study was to explore the feasibility of researching community based yoga classes in Type 2 diabetes with a view to informing the design of a definitive, multi-centre trial Methods The study design was an exploratory randomised controlled trial with in-depth process evaluation. The setting was two multi-ethnic boroughs in London, UK; one with average and one with low mean socio-economic deprivation score. Classes were held at a sports centre or GP surgery. Participants were 59 people with Type 2 diabetes not taking insulin, recruited from general practice lists or opportunistically by general practice staff. The intervention group were offered 12 weeks of a twice-weekly 90-minute yoga class; the control group was a waiting list for the yoga classes. Both groups received advice and leaflets on healthy lifestyle and were encouraged to exercise. Primary outcome measure was HbA1c. Secondary outcome measures included attendance, weight, waist circumference, lipid levels, blood pressure, UKPDS cardiovascular risk score, diabetes-related quality of life (ADDQoL), and self-efficacy. Process measures were attendance at yoga sessions, self-reported frequency of practice between taught sessions, and qualitative data (interviews with patients and therapists, ethnographic observation of the yoga classes, and analysis of documents including minutes of meetings, correspondence, and exercise plans). Results Despite broad inclusion criteria, around two-thirds of the patients on GP diabetic registers proved ineligible, and 90% of the remainder declined to participate. Mean age of participants was 60 +/- 10 years. Attendance at yoga classes was around 50%. Nobody did the exercises regularly at home. Yoga teachers felt that most participants were unsuitable for 'standard' yoga exercises because of limited flexibility, lack of basic fitness, co-morbidity, and lack of confidence. There was a small fall in HbA1c in the yoga group which was not statistically significant and which was not sustained six months later, and no significant change in other outcome measures. Conclusion The benefits of yoga in type 2 diabetes suggested in some previous studies were not confirmed. Possible explanations (apart from lack of efficacy) include recruitment challenges; practical and motivational barriers to class attendance; physical and motivational barriers to engaging in the exercises; inadequate intensity and/or duration of yoga intervention; and insufficient personalisation of exercises to individual needs. All these factors should be considered when designing future trials. Trial registration National Research Register (1410) and Current Controlled Trials (ISRCTN63637211).</p

Inducible liver-specific knockdown of protein tyrosine phosphatase 1B improves glucose and lipid homeostasis in adult mice.

AIMS/HYPOTHESIS Protein tyrosine phosphatase 1B (PTP1B) is a key negative regulator of insulin signalling. Hepatic PTP1B deficiency, using the Alb-Cre promoter to drive Ptp1b deletion from birth in mice, improves glucose homeostasis, insulin sensitivity and lipid metabolism. The aim of this study was to investigate the therapeutic potential of decreasing liver PTP1B levels in obese and insulin-resistant adult mice. METHODS Inducible Ptp1b liver-specific knockout mice were generated using SA-Cre-ER(T2) mice crossed with Ptp1b floxed (Ptp1b(fl/fl)) mice. Mice were fed a high-fat diet (HFD) for 12 weeks to induce obesity and insulin resistance. Tamoxifen was administered in the HFD to induce liver-specific deletion of Ptp1b (SA-Ptp1b(-/-) mice). Body weight, glucose homeostasis, lipid homeostasis, serum adipokines, insulin signalling and endoplasmic reticulum (ER) stress were examined. RESULTS Despite no significant change in body weight relative to HFD-fed Ptp1b(fl/fl) control mice, HFD-fed SA-Ptp1b(-/-) mice exhibited a reversal of glucose intolerance as determined by improved glucose and pyruvate tolerance tests, decreased fed and fasting blood glucose and insulin levels, lower HOMA of insulin resistance, circulating leptin, serum and liver triacylglycerols, serum NEFA and decreased HFD-induced ER stress. This was associated with decreased glycogen synthase, eukaryotic translation initiation factor-2α kinase 3, eukaryotic initiation factor 2α and c-Jun NH2-terminal kinase 2 phosphorylation, and decreased expression of Pepck. CONCLUSIONS/INTERPRETATION Inducible liver-specific PTP1B knockdown reverses glucose intolerance and improves lipid homeostasis in HFD-fed obese and insulin-resistant adult mice. This suggests that knockdown of liver PTP1B in individuals who are already obese/insulin resistant may have relatively rapid, beneficial therapeutic effects

Antisense oligonucleotide and thyroid hormone conjugates for obesity treatment

Using the principle of antibody-drug conjugates that deliver highly potent cytotoxic agents to cancer cells for cancer therapy, we here report the synthesis of antisense-oligonucleotides (ASO) and thyroid hormone T3 conjugates for obesity treatment. ASOs primarily target fat and liver with poor penetrance to other organs. Pharmacological T3 treatment increases energy expenditure and causes weight loss, but is contraindicated for obesity treatment due to systemic effects on multiple organs. We hypothesize that ASO-T3 conjugates may knock down target genes and enrich T3 action in fat and liver. Two established ASOs are tested. Nicotinamide N-methyltransferase (NNMT)-ASO prevents diet- induced obesity in mice. Apolipoprotein B (ApoB)-ASO is an FDA approved drug for treating familial hypercholesterolemia. NNMT-ASO and ApoB-ASO are chemically conjugated with T3 using a non- cleavable sulfo-SMCC linker. Both NNMT-ASO-T3 (NAT3) and ApoB-ASO-T3 (AAT3) enhance thyroid hormone receptor activity. Treating obese mice with NAT3 or AAT3 decreases adiposity and increases lean mass. ASO-T3 enhances white fat browning, decreases genes for fatty acid synthesis in liver, and shows limited effects on T3 target genes in heart and muscle. Furthermore, AAT3 augments LDL cholesterol-lowering effects of ApoB-ASO. Therefore, ASO and hormone/drug conjugation may provide a novel strategy for obesity and hyperlipidemia treatment

Role of glucose and insulin loads to the exercising limb in increasing glucose uptake and metabolism

To assess the contributions of glucose load to the working hindlimb and local contraction-related events (changes related to the microvasculature and/or intrinsic muscle metabolic properties) to the exercise-induced increases in muscle glucose uptake and metabolism in vivo, dogs were studied with somatostatin infused to suppress insulin release, and glucose and insulin were replaced 1) during rest and treadmill exercise at rates that recreate limb glucose and insulin loads evident during exercise (n = 5), 2) at rest to selectively normalize the limb glucose load to rates present during exercise while retaining basal limb insulin loads (GL, n = 5), or 3) at rest to normalize both the limb glucose and insulin loads to those present during exercise (IGL, n = 5). Limb arteriovenous difference and isotopic ([U-14C]glucose) techniques were used to quantify muscle glucose uptake and metabolism. Limb glucose load rose from 819 +/- 141 mumol/min in the basal state to 1,568 +/- 190 mumol/min with exercise. Limb glucose loads were 1,423 +/- 88 and 1,502 +/- 165 mumol/min in GL and IGL. The limb insulin load rose from basal rates of 12.9 +/- 2.3 to 22.9 +/- 5.9 nmol/min during exercise. Limb insulin loads were similar to basal loads in GL (8.8 +/- 1.9 nmol/min) and exercise in IGL (28.2 +/- 5.5 nmol/min).(ABSTRACT TRUNCATED AT 250 WORDS) </jats:p

Acute adaptation of carbohydrate metabolism to decreased arterial PO2

To assess the interaction of arterial PO2 (PaO2) and glucose metabolism, conscious 18-h-fasted dogs with chronically implanted sampling catheters (carotid artery, iliac vein) and flow probe (external iliac artery) were studied during inspiration of air containing 21 (n = 9), 14 (n = 6), 11 (n = 4), or 8% (n = 5) O2. Isotopic and arteriovenous methods were used to assess carbohydrate metabolism. PaO2 was 103 +/- 3, 64 +/- 4, 45 +/- 4, and 30 +/- 1 mmHg with decreased inspired O2. Although limb O2 delivery was reduced (51 +/- 6, 42 +/- 8, 39 +/- 7, and 34 +/- 5 ml/min), limb O2 uptake was not compromised. Plasma insulin was 9 +/- 1, 8 +/- 2, 14 +/- 2, and 16 +/- 3 microU/ml, and glucagon was 53 +/- 3, 49 +/- 3, 64 +/- 5, and 101 +/- 7 pg/ml with decreasing O2. Plasma epinephrine and cortisol were increased whereas norepinephrine was unaffected. Glycemia was unaffected by reduced O2, whereas hepatic glucose output (14 +/- 1, 19 +/- 3, 21 +/- 1, and 22 +/- 1 mumol.kg-1.min-1) and glucose disappearance (14 +/- 2, 18 +/- 3, 20 +/- 1, and 22 +/- 2 mumol.kg-1.min-1) rose similarly. Limb glucose uptake (LGU) rose (21.5 +/- 4.7, 21.2 +/- 5.6, 30.6 +/- 4.7, and 45.3 +/- 9.7 mumol/min) with decreasing O2 because of greater fractional extraction (0.023 +/- 0.005, 0.024 +/- 0.005, 0.031 +/- 0.004, and 0.043 +/- 0.004). Of the increased LGU, approximately 33 and 67% were metabolized oxidatively and nonoxidatively.(ABSTRACT TRUNCATED AT 250 WORDS)</jats:p