Novel Therapies in Type 2 Diabetes: Insulin Resistance

Review

Novel therapies in type 2 diabetes: insulin resistance

Abd A Tahrani Abstract MD, MRCP, PhD, Institute of Metabolism and Systems Insulin resistance plays an important role in the pathogenesis of type 2 diabetes and Research, University of Birmingham, Birmingham, UK; cardiovascular disease. Obesity is a major risk factor for the development of insulin Centre of Endocrinology, Diabetes and Metabolism, resistance. Hence, treating obesity with lifestyle interventions is the cornerstone of managing Birmingham Health Partners, Birmingham, UK; Department of Diabetes and Endocrinology, insulin resistance. However, when lifestyle interventions fail to produce sustainable impact, Birmingham Heartlands Hospital, Birmingham, UK then pharmacotherapy and/or bariatric surgery can produce significant improvements in weight, insulin resistance and glycaemic measures. Ectopic fat in the liver and muscle is one of the main mechanisms via which obesity impacts on insulin sensitivity. Hence, there are Correspondence to: currently multiple therapeutic interventions in development that aim to improve ectopic fat. Abd A Tahrani, Department of Diabetes and With better understanding of the insulin signalling pathways, multiple agents are under Endocrinology, Birmingham Heartlands Hospital, development targeting different components of this pathway from the level of insulin Birmingham B9 5SS, UK; email: [email protected] receptor to the level of protein kinase B activation and the translocation of glucose transporters. The development of these agents has been slow due to the complexity of the Received: 1 May 2017 insulin signalling pathway, the multiple negative feedback signals and the fact that the Accepted in revised form: 8 May 2017 molecules involved in insulin signalling are also involved in other pathways such as cell survival and apoptosis. Sleep-related disorders are increasingly recognised as independent risk factors for the development of insulin resistance and type 2 diabetes; targeting sleep-related disorders as a treatment strategy for insulin resistance is under evaluation. In this article, I will briefly review the future treatments of insulin resistance that are in the pipeline, and I will also briefly review the role of bariatric surgery and sleep-related disorders in the treatment of insulin resistance. Copyright © 2017 John Wiley & Sons. Practical Diabetes 2017; 34(5): 161–166 Key words type 2 diabetes; insulin resistance; obesity; sleep

Introduction have multiple contraindications and Type 2 diabetes (T2D) is characterised their efficacy is not sustainable in the by chronic hyperglycaemia caused by long run.7 Hence there is a need reduction in insulin secretion as a result for more therapies targeting IR in of β-cell dysfunction and impaired insu- line with the improvements in the lin action as a result of insulin resistance understanding of IR pathogenesis. (IR).1 IR results in impaired glucose However, it must be emphasised that uptake in the muscle, liver and adipose lifestyle interventions and weight loss tissue, reduced glycogen synthesis in remain the cornerstone of managing the liver and muscle, increased hepatic IR and T2D.8 gluconeogenesis and increased lipolysis In this article, I will provide an and release of fatty acids (FAs) and overview of the pathogenesis of IR and glycerol.2 Glycerol and FA contribute to how this is related to the development and worsen IR, gluconeogenesis and of new treatments. In addition, I will ectopic fat accumulation in the liver briefly highlight the importance of and the muscle.2 IR also contributes targeting obesity and more novel life- to the development of cardiovascular style factors that can impact on IR such disease as it is associated with hyperten- as sleep-related disorders. A more sion, dyslipidaemia, hypercoagulability, detailed review of IR pathogenesis can sympathetic activation and reduced be found in Samuel and Shulman.2,9 insulin-dependent nitric oxide production and increased endothelin-1.3–5 The pathogenesis of insulin Hence, IR is an important treatment resistance target in patients with T2D.6 In brief, insulin binding to the α-sub- Metformin and pioglitazone are unit of the insulin receptor results in the main available pharmacological the phosphorylation of the insulin agents to improve insulin sensitivity receptor substrates 1 and 2 (IRS-1 in patients with T2D, both are associ- and -2) which leads, via several inter- ated with variety of adverse events, mediary steps, to activation of protein

Muscle Insulin

Insulin Insulin mimetics receptor Inositol IKKB inhibitors Interleukin 6 derivatives Glycoprotein 1 Plasma membrane SOCS3 PP2C PIP2 p85 PTEN IKKB PTEN p110 inhibitors PIP SHIP-2 JNK inhibitors JNK Pl3K 3 SHIP-2 inhibitors IRS proteins p70S6K Protein PTP-1B synthesis Grb PDK1 and 2 Ceramide SOS PKC Ceramide PTP-1B inhibitors Ras inhibitors Raf mTOR Akt FAs MEK DAG MAPK Fatty ↑ Glucose acids FOX01 ↓ Insulin ROS GLUT4 GSK3 eNOS translocation Gene transcription AMPK Antioxidants Endothelial Glucose uptake function and metabolism PPAR/RXR AMPK agonists, PGC-1 α activation

NOTES. Dashed line with a bar at the end means inhibition. Solid line with an arrowhead means a stimulatory effect. SOCS-3 = suppressor of cytokine signalling 3. PIP2 = phosphatidylinositol-3,4-bisphosphate. PP2C = pyruvate dehydrogenase phosphatase (protein phosphatase 2C). TNFα = tumour necrosis factor α. JNK = c-Jun N-terminal kinase. IRS = insulin receptor substrate. PI3K = phosphatidylinositol 3-kinase. PIP3 = phosphatidylinositol-3,4,5- trisphosphate. PTEN = protein phosphatase. SHIP-2 = Src homology-2-inositol phosphatase. PTP-1B = protein tyrosine phosphatase 1B. IKKB = inhibitor κ-B kinase-β. PDK = phosphoinositide-dependent protein kinase. Grb = growth-factor-receptor-binding protein. SOS = sons of sevenless. Ras = guanosine trisphosphatase. Raf = serine-threonine protein kinase. MEK = mitogen-activated protein kinase kinase. MAPK = mitogen-activated protein kinase. PKC = protein kinase C. mTOR = mammalian target of rapamycin. Akt = protein kinase B. FAs = fatty acids. DAG = diacylglycerol. ROS = reactive oxygen species. FOXO1 = forkhead box protein O1A. eNOS = endothelial nitric oxide synthase. GLUT = glucose transporter isoform. GSK3 = glycogen synthase kinase 3. PPAR = peroxisome-proliferator-activated receptor. RXR = retinoid-X receptor. PGC-1α = PPAR coactivator 1α. AMPK = adenosine monophosphate- activated protein kinase.

Figure 1. Potential sites for intervention in intracellular pathways of insulin signalling and examples of therapeutic targets. (Adapted from Bailey CJ. Diab Vasc Dis Res 2007;4:20–31)13 kinase B (Akt).8 Akt activation results for the development of IR and T2D.10 lean individuals with and without in the translocation of the glucose Obesity contributes to the develop- T2D.2 The impact of IMCL and transporters (GLUTs) to the cell ment of IR via several mechanisms NAFLD on IR is mediated via diacyl surface, allowing glucose entry, and (Figure 2).2,9,10 glycerol (DAG) accumulation leading the activation of glycogen synthase to Ectopic fat and lipids accumula- to protein kinase C (PKC) activation stimulate the storage of glucose as tion in the liver (non-alcoholic fatty which impairs insulin-stimulated glycogen.9 IR can result from deficits liver disease [NAFLD]) and skeletal tyrosine phosphorylation of IRS-1 in any part of the insulin signalling muscle (intramyocellular lipid and the consequent activation of pathway resulting in inadequate [IMCL]) plays an important role in phosphatidylinositol 3-kinase (PI3K) response to insulin (Figure 1).7 the pathogenesis of IR.2,9 IMCL has resulting in reduction in Akt.2,11 IR results from complex and multi- been shown to be a better predictor Ectopic fat accumulation is factorial interactions between the of IR than fat mass and several studies caused by increased supply of FAs genes and the environment,10 but have shown that IMCL blocks glucose as a result of increased lipolysis obesity remains the major risk factor entry to the muscles in obese and caused by increased adipose tissue

Liver Insulin Fibroblast growth factor 21

PKCε PKC inhibitors 1 Gluconeogenesis PKCζ IR Akt2 DAG Glucose IRS1/2 ATGL PKCε Akt2 TAG STAT3 PEP PP2A PNPLA3 FOXO Akt2 PKCδ CO Malate FA-CoA CPT1 2 Ceramide Ceramides IL6 TCA Increased hepatic synthesis SREBP1c mitochondrial CS Pyruvate PDH IL6R Sphingosine uncoupling 2 Lipogenesis LPA DAG 3 DGAT2 SPT FA-CoA GPAT G3P LPS/SFA Serine C/EBP TAG TLR4 IKK BiP eIF2 γ IRE1α IKKB inhibitors α β XBP1 BiP BiP PERK TNFα JNK1 FACS XBP1 TNFR CD36 FATP5&2

TAG LPL Fatty acids

Activation Inactivation Transcriptional activation Transcriptional suppression

NOTES. Insulin activates the insulin receptor (IR) tyrosine kinase, which subsequently tyrosine phosphorylates IRS1 and 2. Through a set of intermediary steps, this leads to activation of Akt2. Akt2 can promote glycogen synthesis (not shown), suppress gluconeogenesis, and activate de novo lipogenesis (DNL). This central signalling pathway is connected to multiple other cellular pathways that are designated by numbers 1–3. Key lipid synthesis pathways are juxtaposed within this domain and are regulated by them. (1) The green-shaded areas represent mechanisms for lipid-induced insulin resistance – notably, diacylglycerol-mediated activation of PKCε and subsequent impairment of insulin signalling, as well as ceramide-mediated increases in PP2A and increased sequestration of Akt2 by PKCζ. Impaired Akt2 activation limits the inactivation of FOXO1 and allows for increased expression of key gluconeogenesis enzymes. Impaired Akt2 activity also decreases insulin-mediated glycogen synthesis (not shown). (2) The yellow areas depict several intracellular inflammatory pathways – notably, the activation of IKK, which may impact ceramide synthesis, and the activation of JNK1, which may impair lipogenesis. (3) The pink area depicts activation of the unfolded protein response (UPR) that can lead to increased lipogenesis via XBP1s and also increased gluconeogenesis via C/EBP. The endoplasmic reticulum (ER) membranes also contain key lipogenic enzymes and give rise to lipid droplets. Proteins that regulate the release from these droplets (e.g. ATGL and PNPLA3) may modulate the concentration of key lipid intermediates in discrete cell compartments. CS = ceramide synthase; DNL = de novo lipogenesis; FA-CoA = fatty acyl CoA; G3P = glycerol 3-phosphate; LPA = lysophosphatidic acid; SPT = serine palmitoyl transferase; TAG = triacylglycerol; TCA = tricarboxylic acid cycle; PEP = phosphoenolpyruvate.

Figure 2. Hepatic insulin resistance and potential therapeutic targets. (Adapted from Samuel VT, Shulman GI. Cell 2012;148:852–71)9 inflammation.11 FAs are esterified Pharmacotherapy for insulin ectopic fat, inflammation or adipo upon cellular entry to form acylglyc- resistance under development kines), or the deficits in the insulin erols or ceramides, which can reduce Improving insulin sensitivity can be signalling pathway (such as activating Akt activation.9,12 In addition, the achieved by addressing the causes of IR the insulin receptor or potentiating the inflammation associated with obesity (such as obesity, sedentary behaviour or phosphorylation that occurs following can activate JNK-1, that can block the more emerging factors such as sleep the insulin receptor activation). IRS-1, and IKK that can lead to disorders), or the mechanisms via Currently available treatments for IR increased ceramides.9 which obesity impacts on IR (such as exert their impact by combinations of

the above-mentioned mechanisms. For more recent study using ob/ob mice Adipokines. Adiponectin is an insu- example, metformin increases the and a methionine- and choline- lin sensitising adipokine that phosphorylation of the insulin receptor deficient (MCD) diet to induce improves insulin sensitivity by activat- by increasing the β-subunit tyrosine steatohepatitis, LY2405319 attenu- ing AMPK and peroxisome prolifera- kinase activity (TKA) and activation of ated non-alcoholic steatohepatitis tor-activated receptor (PPAR)-α.21 adenosine 5’-monophosphate-activated (NASH) progression and enhanced AdipoRon, an orally-active adipo protein kinase (AMPK), which inhibits hepatic mitochondrial function.17 nectin receptors 1 and 2 agonist, tyrosine phosphatases that are responsi- Another therapeutic option to improved IR and glucose levels in ble for the dephosphorylation of the address NAFLD is the inhibition of high-fat diet-fed (HFD) mice and insulin receptor.13,14 In addition, AMPK acetyl-CoA carboxylase (ACC). ACC ameliorated diabetes in db/db activation results in decreased lipolysis catalyses the ATP-dependent carbox- mice.22 Apelin is another adipokine in adipose tissue, decreased hepatic ylation of acetyl-CoA to malonyl-CoA, that also improves insulin sensitivity lipogenesis, increased FA oxidation in which is the rate-limiting step in FA by AMPK activation.23 Apelin admin- the liver and muscle, and increased synthesis and also plays a role in FA istration in HFD obese mice for four glucose uptake.13 Thiazolidinediones oxidation.18 ACC has two isozymes: weeks improved fat mass, glycaemia, improve IR by reducing inflammation, ACC1 which is a cytosolic enzyme and triglycerides and mice were increasing adiponectin production and present in the liver and adipose protected from hyperinsulinaemia increasing lipogenesis in the subcutane- tissue, and ACC2 which is associated compared with placebo.24 ous depots, resulting in reduction in with the mitochondria and present FA release and improvements in in the liver, heart and skeletal Resveratrol. Resveratrol is a phyto ectopic fat.14 muscle.18 In the liver, the malonyl- phenol found in many plants, CoA formed in the cytoplasm by especially red grape, and is a potent Targeting mechanisms linking ACC1 is used primarily for FA synthe- sirtuin 1 activator. Sirtuin 1 improves obesity to insulin resistance sis while the malonyl-CoA formed at several processes that are involved Targeting ectopic fat. Fibroblast the mitochondrial surface by ACC2 in IR pathogenesis including inflam- growth factor 21 (FGF21) has been regulates mitochondrial FA oxida- mation and oxidative stress.25 gaining much interest recently as a tion.18 Several rodent studies have Resveratrol has been shown to regulator for lipid and glucose shown favourable impact of ACC activate AMPK, increase PPAR-γ metabolism that can reduce ectopic inhibition on NAFLD and T2D.2 coactivator (PGC-1α) levels, increase fat and as a result improve IR. ND-630, an ACC inhibitor, has been mitochondrial activity and respira- Rodents studies have shown that shown to reduce FA synthesis and tion, and reduce intramyocellular FGF21 can reduce hepatic and stimulate FA oxidation in human and intrahepatic lipid content.26 In peripheral IR and liver triglycerides hepatic HepG2 cells.18 Chronic addition, resveratrol has been shown in chow- and high-fat fed wild-type administration of ND-630 to rats with to reduce lipolysis and FA levels post- mice.15 These improvements in IR diet-induced obesity reduced hepatic prandially.26 A meta-analysis of 11 were associated with increased fat and improved insulin sensitivity RCTs showed that resveratrol had no whole-body energy expenditure and and lipids profile.18 When ND-630 effect on IR or glycaemic measures reduction in hepatocellular and was administered to Zucker diabetic in people without diabetes but low- myocellular DAG content and PKC fatty rats, it reduced hepatic steatosis, ered HbA1c (average 0.8%) and IR in activation in liver and skeletal muscle and improved HbA1c by 0.9%.18 patients with T2D.27 However, only with no effect on ceramides.15 Another novel therapeutic two of these RCTs were in patients LY2405319 is an FGF21 analogue approach to improve hepatic steato- with T2D, the sample sizes were <70 that has reached clinical develop- sis is to increase hepatic mitochon- patients for these studies, and the ment. In a phase Ib 28-day ran- drial uncoupling by promoting treatment duration was for three domised controlled trial (RCT), 47 hepatic triglyceride oxidation, but months. So more well-designed RCTs obese patients with T2D (44% whites, older generations of these agents of larger sample size and adequate diabetes duration 7.4 years, age 57.7 were associated with an unaccept- longer follow up are needed. years, BMI 32.1kg/m2, HbA1c 7.96%) able adverse events profile, including were randomised to placebo vs death, but newer agents are showing Inhibitor kappa-B kinase-beta (IKKB) multiple doses of LY2405319.16 The a better safety profile.19 Controlled- inhibitors. Inflammatory cytokines results of this RCT were consistent release mitochondrial protonophore activate IKKB which results in dephos- with the rodent studies and showed (CRMP), that produces mild hepatic phorylation of the Akt by increasing that LY2405319 (compared to plac mitochondrial uncoupling, reduced ceramides production.9 Administration ebo) reduced fasting glucose (by hypertriglyceridaemia, insulin resist- of IKKB inhibitor (IMD-0354) to KKAy 0.4–0.6mmol/L) and insulin levels ance, hepatic steatosis, and liver mice receiving HFD improved hyper and increased adiponectin levels.16 fibrosis.19 Similarly, niclosamide, glycaemia, IR and adiponectin levels In addition, LY2405319 resulted which is FDA approved as an anthel- after seven days of treatment.28 in modest decrease in weight (by mintic drug, has been shown to have 1.5–1.8kg) and improved lipid a favourable impact on IR and Targeting the insulin receptor profile (reduced LDL by 20–30% hepatic steatosis high-fat diet mice These compounds can generally be and triglycerides by 44–46% and and it improved glycaemic control in divided into agents that can stimulate increased HDL by 15–20%).16 In a the db/db mice.20 the insulin receptor independently

of insulin binding to the receptor and synthesised in mitochondria from causing a reduction in Akt phospho- agents that can potentiate the insu- octanoic acid and is a cofactor for rylation.43 PTEN is a tumour suppres- lin-initiated tyrosine phosphorylation mitochondrial α-ketoacid dehydroge- sor protein.43 Patients with Cowden of the insulin receptor β-subunit and nases, and thus serves a critical role in syndrome, a rare cancer-predisposing the IRS 1/2, or prevent their dephos- mitochondrial energy metabolism.8 condition with PTEN loss of function phorylation.29 Some of these agents In rat hepatocytes, ALA directly binds mutation, were found to have can be given orally.7,8 to and activates the tyrosine kinase increased Akt phosphorylation and domain of the insulin receptor result- better insulin sensitivity compared to Demethylasterriquinone and its ing in activation of the insulin signal- age, sex and BMI matched healthy derivatives. Demethylasterriquinone ling pathway and increasing GLUT-4 controls.44,45 Similar results were (DMAQ) B1 (L-783,281 or compound translocation.37 In a small RCT found in rodent studies using PTEN 1) is a benzoquinone derivative derived (n=107) of patients with T2D who inhibitors.46 PTEN inhibitors need to from the fungus Pseudomassari.30 It were randomised to supplements be highly specific and only inhibit binds to the β-subunit of the insulin including ALA vs placebo for three PTEN partially in order to have an receptor and initiates the insulin signal- months, ALA improved HbA1c by acceptable safety profile. ling pathways without the need of insu- 0.6%, and lowered LDL and triglycer- lin.31 However, this compound had a ides and HOMA-IR without an effect Inositol phosphatases inhibitors. quinone moiety that when in contact on weight.38 Type-II SH2-domain-containing with high energy resulted in the pro- inositol 5-phosphatase (SHIP2) is a duction of free radicals, which made it Protein tyrosine phosphatase 1B member of the inositol polyphos- unsuitable for humans.13,32 As a result, (PTP-1B) inhibitors. PTP-1B termi- phate 5-phosphatase family. SHIP2 non-quinone DMAQ B1 derivatives nates the insulin receptor activity by contributes to the conversion of were developed. One example is dephosphorylating the insulin recep- PIP3 to PIP2 resulting in the inhibi- D-410639, which is 128-fold less cyto- tor β-subunit, and the IRS1/2; hence tion of Akt phosphorylation.47 toxic than DMAQ B1 and was able to inhibiting PTP-1B would potentiate Rodent studies showed that SHIP2 activate the recombinant human insu- insulin action when insulin is bound mutations are associated with lin receptor on the CHO cell line.30 In to the α-subunit.13 Several studies improved insulin sensitivity and addition, D-410639 inhibited epider- using different compounds showed increased concentration of GLUT- mal growth factor receptor (EGF-R/ that PTP-1B inhibition increased 4.42,48 Inhibiting SHIP2 using an ErbB1) which is involved in vascular insulin receptor and IRS phosphoryl- antisense oligonucleotide has also dysfunction in patients with diabetes; ation, enhanced insulin actions, been shown to improve IR and Akt which suggests that this compound improved IR, and improved hypergly- phosphorylation.49 Several studies might have vascular benefits.33 Another caemia in rodent studies.8,39 However, in humans showed that polymor- promising compound is compound the clinical development of these phisms in the SHIP2 gene were 5,8-diacetyloxy-2,3-dichloro-1,4-naph- agents proved to be challenging due associated with T2D.50 thoquinone which also binds to the to adverse events and lack of selectiv- kinase domain of the insulin receptor ity.29 High selectivity is essential as Inositol derivatives. Myo-inositol to trigger insulin action.34 This oral PTP1-B and T-cell protein tyrosine forms the structural basis for PIP2 compound improved glucose levels in phosphatase (TCPTP), which is abun- and PIP3. Pinitol (3-O-methyl-chiro- wild-type C57BL/6J mice and db/db dantly expressed in haematopoietic inositol), from the plant Bougainvillea and ob/ob mice without evidence cells, share >70% amino acid sequence spectabilis, has been shown to improve of toxicity.34 identity in the catalytic domain.40 IR and lower glucose levels in animal studies; these effects were inhibited XMetA. XMetA is a high-affinity, PKC inhibitors. As discussed above, by the presence of PI3K inhibition.51 allosteric, human monoclonal anti- PKC activation via increase in DAG In humans, the results of RCTs were body to the insulin receptor that does reduces insulin-mediated IRS and not consistent; while some studies not compete with insulin binding.35 It Akt phosphorylation and PI3K acti- showed no effect on hyperglycaemia activates the insulin receptor but not vation leading to IR.41 Studies in or IR,52 others showed reduced the IGF1 receptor, and it mimics the obese and diabetic rodents showed HbA1c and HOMA-IR as well as glucoregulatory but not the mitogenic that treatment with ruboxistaurin favourable impacts on LDL/HDL actions of insulin.35 In diet-induced (LY333531), a selective PKCβ inhibi- ratio and blood pressure.53,54 obese mice, XMetA normalised fasting tor, improved insulin-stimulated Akt D-chiro-inositol and myo-inositol glucose, corrected glucose tolerance phosphorylation and IR and insulin have been shown to improve IR in and improved non-HDL cholesterol stimulated vascular contraction.42 women with polycystic ovarian syn- with no weight gain or hypoglycae- drome, although this has not trans- mia.35 Similar results were found Targeting post-insulin lated into better clinical outcomes in recently in a study in diabetic cynomo- receptor signalling terms of ovulation and fertility.55 lgus monkeys.36 PTEN inhibitors. The phosphatase In a recent meta-analysis of five and tensin homolog (PTEN) dephos- trials containing 513 participants, Alpha-lipoic acid (ALA). ALA (1, phorylates phosphatidylinositol (3,4,5)- myo-inositol reduced the risk of 2-dithiolane-3-pentanoic acid) is trisphosphate (PIP3) to phosphatidy- gestational diabetes (risk ratio 0.29; a naturally occurring compound linositol 4,5-bisphosphate (PIP2), 95% CI 0.19–0.44).56

Targeting the underlying causes of insulin resistance Key points Obesity Obesity is a major risk factor for l Obesity is an important contributor to the development of insulin resistance (IR) via T2D; as a result, interventions (life- multiple mechanisms, particularly ectopic fat deposition style, pharmacotherapy, bariatric l The increasing understanding of the pathogenesis of IR allowed the development of surgery) aimed at causing weight loss several agents targeting difference aspects of the pathogenesis of IR (from as little as 5%) and reduction l The development of these agents has been relatively slow due to the complexity of IR in visceral fat result in significant pathogenesis and because many components of the insulin signalling pathway are improvements in T2D and/or IR.8,57 involved in other pathways such as cell survival and apoptosis More recently, bariatric surgery l Lifestyle interventions and treating obesity remain the cornerstone of treating IR became an important treatment l Sleep-related disorders are an increasingly recognised treatment target for IR option in patients with T2D, resulting in long-term sustained weight was also associated with higher HbA1c that target deficits in proximal loca- loss with significant improvements and higher IR in patients with type 1 tions of the insulin signalling pathway in glycaemic parameters, IR and diabetes (based on hyperinsulinaemic might result in a broader spectrum of cardiovascular disease risk factors.8,58 euglycaemic clamp).67 In laboratory- benefits compared to targeting distal The impact of bariatric surgery in based studies, acute sleep restriction in locations; but the impact of the patients with T2D was superior to healthy lean individuals resulted in IR negative feedback exerted by distal medical care in several RCTs.59–61 and dysglycaemia.68 signalling steps on earlier ones might The improvements in glycaemic Interventional studies assessing the lessen such benefits.7,13 In addition, control after bariatric surgery impact of sleep duration manipulation the insulin signalling pathway is occurred in the context of reduction on IR and glycaemic control are ongo- involved in cell survival and other in the use of insulin and other glu- ing, but a recent small study of 10 functions and hence any interven- cose-lowering agents. More details young adults with habitual sleep dura- tions need to be specific, partial and about the mechanism of action and tion <6.5 hours/night showed that reversible.6,8,13 Targeting obesity the impact of bariatric surgery in extending sleep duration by 1.6 hours/ remains a major step in the manage- T2D can be found in Papamargaritis night for two weeks in their home ment of patients with T2D and IR, but et al.62 and Miras and le Roux.63 environment was associated with a lifestyle interventions are difficult to 14% decrease in overall appetite and a maintain on the long term. As a Sleep-related disorders 62% decrease in desire for sweet and result, bariatric surgery is an impor- An emerging important risk factor salty foods,69 suggesting that such tant option to consider in some for the development of IR and interventions might have important patients. Sleep-related disorders are T2D is sleep-related disorders. In a metabolic effects. also emerging as an important con- meta-analysis of 36 studies (includ- OSA is very common in patients tributor to IR, but interventional ing 1 061 555 participants) the with T2D and is associated with IR studies are awaited in relation to the pooled relative risks (RR, [95% CI]) and worse glycaemic control.70 impact of sleep duration manipula- for developing diabetes were 1.48 Several meta-analyses have shown that tion on IR. The data about the impact (95% CI 1.25–1.76), 1.18 (1.10–1.26) OSA treatment (continuous positive of CPAP on IR in patients with OSA and 1.36 (1.12–1.65) for sleeping ≤5 airway pressure; CPAP) improves IR are encouraging, but CPAP compli- hours, 6 hours, and ≥9 hours/day, in patients with and without T2D.71 ance is challenging in real life and the respectively. The RRs (95% CI) for impact of CPAP on glycaemic control developing diabetes in patients with Summary and conclusions is controversial. poor sleep quality, obstructive sleep IR plays an important role in the apnoea (OSA) and shift work were pathogenesis of T2D and associated Declaration of interests 1.40 (1.21–1.63), 2.02 (1.57–2.61) cardiovascular disease. Improving IR AAT has received honoraria for advi- and 1.40 (1.18–1.66), respectively.64 is an important treatment target in sory boards and lectures, and was Another meta-analysis showed simi- patients with T2D and pre-diabetes/ supported to attend conferences by lar results in that short sleep dura- the metabolic syndrome. As our AstraZeneca, Boehringer-Ingelheim, tion was associated with an increased understanding of the pathogenesis of Bristol-Myers Squibb, Eli Lilly, Janssen, risk of developing diabetes as well as IR improved, new pharmacological Novo Nordisk, and Sanofi Aventis. an increased risk of mortality, obesity agents were developed. But many of AAT is a Clinician Scientist sup- and cardiovascular disease.65 these agents are in the pre-clinical ported by the National Institute for In patients with T2D, short and phase and it remains unclear which Health Research (NIHR). The views long sleep duration and poor sleep will progress to clinical trials in expressed in this publication are quality were associated with higher humans. Developing new treatments those of the author and not neces- HbA1c, as was shown in a recent for IR is challenging due to the com- sarily those of the NHS, the NIHR, meta-analysis (weighted mean differ- plexity of IR pathogenesis and the or the Department of Health. ence 0.23% [0.10–0.36], 0.13% [0.02– presence of multiple feedback loops 0.25], 0.35% [0.12–0.58]) for short which make it difficult to predict the References sleep, long sleep and poor sleep qual- consequences of a particular inter- References are available online at ity, respectively.66 Short sleep duration vention.8 For example, treatments www.practicaldiabetes.com.

References metabolism and metabolic profile in obese humans. sensitivity in a dietary rat model of the metabolic Cell Metab 2011;14(5):612–22. syndrome. Am J Physiol Endocrinol Metab 2007; 1. DeFronzo RA. From the triumvirate to the ominous 27. Liu K, et al. Effect of resveratrol on glucose control 292(6):E1871–E1878. octet: a new paradigm for the treatment of type 2 and insulin sensitivity: a meta-analysis of 11 50. Viernes DR, et al. Discovery and development of diabetes mellitus. Diabetes 2009;58(4):773–95. randomized controlled trials. Am J Clin Nutr 2014; small molecule SHIP phosphatase modulators. Med 2. Samuel VT, Shulman GI. The pathogenesis of insulin 99(6):1510–9. Res Rev 2014;34(4):795–824. resistance: integrating signaling pathways and sub- 28. Kamon J, et al. A novel IKKβ inhibitor stimulates 51. Croze ML, Soulage CO. Potential role and therapeu- strate flux.J Clin Invest 2016;126(1):12–22. adiponectin levels and ameliorates obesity-linked tic interests of myo-inositol in metabolic diseases. 3. Muniyappa R, Sowers JR. Role of insulin resistance insulin resistance. Biochem Biophys Res Commun Biochimie 2013;95(10):1811–27. in endothelial dysfunction. Rev in Endocr Metab 2004; 323(1):242–8. 52. Bates SH, et al. Insulin-like effect of pinitol. Br J Disord 2013;14(1):5–12. 29. Bailey CJ, et al. Future glucose-lowering drugs for Pharmacol 2000;130(8):1944–8. 4. Ginsberg HN. Insulin resistance and cardiovascular type 2 diabetes. Lancet Diabetes Endocrinol 2016; 53. Ortmeyer HK, et al. Effects of D-chiroinositol added disease. J Clin Invest 2000;106(4):453–8. 4(4):350–9. to a meal on plasma glucose and insulin in hyper 5. Lambert GW, et al. Sympathetic nervous activation in 30. Tsai HJ, Chou SY. A novel hydroxyfuroic acid com- insulinemic rhesus monkeys. Obes Res 1995; obesity and the metabolic syndrome – causes, conse- pound as an insulin receptor activator. Structure and 3(S4):605S–8S. quences and therapeutic implications. Pharmacol activity relationship of a prenylindole moiety to 54. Davis A, et al. Effect of pinitol treatment on insulin Ther 2010;126(2):159–72. insulin receptor activation. J Biomed Sci 2009;16:68. action in subjects with insulin resistance. Diabetes 6. Tahrani AA, et al. Glycaemic control in type 2 diabe- 31. Zhang B, et al. Discovery of a small molecule insulin Care 2000;23(7):1000–5. tes: targets and new therapies. Pharmacol Ther 2010; mimetic with antidiabetic activity in mice. Science 55. Legro RS. Ovulation induction in polycystic ovary 125(2):328–61. 1999;284(5416):974–7. syndrome: Current options. Best Pract Res Clin 7. Tahrani AA, et al. Management of type 2 diabetes: 32. Nankar RP, Doble M. Non-peptidyl insulin mimetics Obstet Gynaecol 2016;37:152–9. new and future developments in treatment. Lancet as a potential antidiabetic agent. Drug Discov Today 56. Zheng X, et al. Relationship between myo-inositol 2011;378(9786):182–97. 2013;18(15):748–55. supplementary and gestational diabetes mellitus: 8. Altaf QA, et al. Novel therapeutics for type 2 diabe- 33. Benter IF, et al. Diabetes-induced renal vascular A meta-analysis. Medicine (Baltimore) 2015; tes: insulin resistance. Diabetes Obes Metab 2015; dysfunction is normalized by inhibition of epidermal 94(42):e1604. 17(4):319–334. growth factor receptor tyrosine kinase. J Vasc Res 57. Magkos F, et al. Effects of moderate and subsequent 9. Samuel VT, Shulman GI. Mechanisms for insulin 2005;42(4):284–91. progressive weight loss on metabolic function and resistance: common threads and missing links. Cell 34. He K, et al. Identification of a molecular activator for adipose tissue biology in humans with obesity. Cell 2012;148(5):852–71. insulin receptor with potent anti-diabetic effects. Metab 2016;23(4):591–601. 10. Kahn SE, et al. Mechanisms linking obesity to insulin J Biol Chem 2011;286(43):37379–88. 58. Sjöström L, et al. Association of bariatric surgery resistance and type 2 diabetes. Nature 2006; 35. Bhaskar V, et al. XMetA, an allosteric monoclonal with long-term remission of type 2 diabetes and 444(7121):840–6. antibody to the insulin receptor, improves glycaemic with microvascular and macrovascular complica- 11. Boura-Halfon S, Zick Y. Phosphorylation of IRS control in mice with diet-induced obesity. Diabetes tions. JAMA 2014;311(22):2297–304. proteins, insulin action, and insulin resistance. Am J Obes Metab 2013;15(3):272–5. 59. Ikramuddin S, et al. Roux-en-y gastric bypass vs Physiol Endocrinol Metab 2009;296(4):E581–E591. 36. Bezwada P, et al. A novel allosteric insulin recep- intensive medical management for the control of 12. Stratford S, et al. Regulation of insulin action by cer- tor-activating antibody reduces hyperglycemia with- type 2 diabetes, hypertension, and hyperlipidemia: amide dual mechanisms linking ceramide accumula- out hypoglycemia in diabetic cynomolgus monkeys. The diabetes surgery study randomized clinical trial. tion to the inhibition of Akt/protein kinase B. J Biol J Pharmacol Exp Ther 2016;356(2):466–73. JAMA 2013;309(21):2240–9. Chem 2004;279(35):36608–15. 37. Diesel B, et al. Alpha lipoic acid as a directly binding 60. Schauer PR, et al. Bariatric surgery versus intensive 13. Bailey CJ. Treating insulin resistance: future pros- activator of the insulin receptor: protection from medical therapy for diabetes – 3-year outcomes. pects. Diab Vasc Dis Res 2007;4(1):20–31. hepatocyte apoptosis. Biochemistry 2007;46(8): N Engl J Med 2014;370(21):2002–13. 14. Tahrani AA, et al. Pharmacology and therapeutic 2146–55. 61. Dixon JB, et al. Adjustable gastric banding and con- implications of current drugs for type 2 diabetes 38. Derosa G, et al. A clinical trial about a food supple- ventional therapy for type 2 diabetes: A randomized mellitus. Nat Rev Endocrinol 2016;12(10):566–92. ment containing α-lipoic acid on oxidative stress controlled trial. JAMA 2008;299(3):316–23. 15. Camporez JP, et al. Cellular mechanisms by which markers in type 2 diabetic patients. Int J Mol Sci 62. Papamargaritis D, et al. Mechanisms of weight loss, FGF21 improves insulin sensitivity in male mice. 2016;17(11):1802. diabetes control and changes in food choices after Endocrinology 2013;154(9):3099–109. 39. Zhang X, et al. A novel protein tyrosine phosphatase gastrointestinal surgery. Curr Atheroscler Rep 2012; 16. Gaich G, et al. The effects of LY2405319, an FGF21 1B inhibitor with therapeutic potential for insulin 14(6):616–23. analog, in obese human subjects with type 2 dia resistance. Br J Pharmacol 2016;173(12):1939–49. 63. Miras AD, le Roux CW. Metabolic surgery: shifting betes. Cell Metab 2013;18(3):333–40. 40. Stuible M, et al. PTP1B and TC-PTP: regulators of the focus from glycaemia and weight to end-organ 17. Lee JH, et al. An engineered FGF21 variant, transformation and tumorigenesis. Cancer Metastasis health. Lancet Diabetes Endocrinol 2014;2(2): LY2405319, can prevent non-alcoholic steatohepati- Rev 2008;27(2):215–30. 141–51. tis by enhancing hepatic mitochondrial function. Am 41. Naruse K, et al. Activation of vascular protein kinase 64. Anothaisintawee T, et al. Sleep disturbances J Transl Res 2016;8(11):4750–63. C-β inhibits Akt-dependent endothelial nitric oxide compared to traditional risk factors for diabetes 18. Harriman G, et al. Acetyl-CoA carboxylase inhibition synthase function in obesity-associated insulin development: Systematic review and meta-analysis. by ND-630 reduces hepatic steatosis, improves insu- resistance. Diabetes 2006;55(3):691–8. Sleep Med Rev 2016;30:11–24. lin sensitivity, and modulates dyslipidemia in rats. 42. Lu X, et al. Protein kinase C inhibition ameliorates 65. Itani O, et al. Short sleep duration and health out- Proc Natl Acad Sci 2016;113(13):E1796–E1805. functional endothelial insulin resistance and vascu- comes: a systematic review, meta-analysis, and 19. Perry RJ, et al. Controlled-release mitochondrial lar smooth muscle cell hypersensitivity to insulin in meta-regression. Sleep Med 2017;32:246–56. protonophore reverses diabetes and steatohepatitis diabetic hypertensive rats. Cardiovasc Diabetol 66. Lee SWH, et al. The impact of sleep amount and in rats. Science 2015;347(6227):1253–6. 2011;10:48. sleep quality on glycemic control in type 2 diabetes: 20. Tao H, et al. Niclosamide ethanolamine improves 43. Butler M, et al. Specific inhibition of PTEN expres- A systematic review and meta-analysis. Sleep Med blood glycemic control and reduces hepatic steato- sion reverses hyperglycemia in diabetic mice. Rev 2017;31:91–101. sis in mice. Nat Med 2014; 20(11):1263-1269. Diabetes 2002;51(4):1028–34. 67. Borel AL, et al. Short sleep duration measured by 21. Yadav A, et al. Role of leptin and adiponectin in insu- 44. Pal A, et al. PTEN mutations as a cause of constitu- wrist actimetry is associated with deteriorated lin resistance. Clinica Chimica Acta 2013;417:80–4. tive insulin sensitivity and obesity. N Engl J Med glycemic control in type 1 diabetes. Diabetes Care 22. Okada-Iwabu M, et al. A small-molecule AdipoR 2012;367(11):1002–11. 2013;36(10):2902–8. agonist for type 2 diabetes and short life in obesity. 45. Pal A, et al. PTEN mutations as a cause of constitu- 68. Leproult R, Van Cauter E. Role of sleep and sleep loss Nature 2013;503(7477):493–9. tive insulin sensitivity and obesity in human beings. in hormonal release and metabolism. Endocr Dev 23. Xu S, et al. Apelin and insulin resistance: another Lancet 2013;381:S13. 2010;17:11–21. arrow for the quiver? J Diabetes 2011;3(3):225–31. 46. Mak LH, Woscholski R. Targeting PTEN using small 69. Tasali E, et al. The effects of extended bedtimes on 24. Attané C, et al. Apelin treatment increases complete molecule inhibitors. Methods 2015;77–78:63–8. sleep duration and food desire in overweight young fatty acid oxidation, mitochondrial oxidative capac- 47. Ishihara H, et al. Molecular cloning of rat SH2- adults: A home-based intervention. Appetite 2014; ity, and biogenesis in muscle of insulin-resistant containing inositol phosphatase 2 (SHIP2) and its 80(0):220–4. mice. Diabetes 2012;61(2):310. role in the regulation of insulin signaling. Biochem 70. Tahrani AA, et al. Obstructive sleep apnoea and dia- 25. Boutant M, Cantó C. SIRT1 metabolic actions: Biophys Res Commun 1999;260(1):265–72. betes: an update. Curr Opin Pulm Med 2013;19(6): Integrating recent advances from mouse models. 48. Clément S, et al. The lipid phosphatase SHIP2 controls 631–8. Mol Metab 2014;3(1):5–18. insulin sensitivity. Nature 2001;409(6816):92–7. 71. Tahrani AA. Obstructive sleep apnoea and vascular 26. Timmers S, et al. Calorie restriction-like effects of 30 49. Buettner R, et al. Antisense oligonucleotides against disease in patients with type 2 diabetes. Eur days of resveratrol supplementation on energy the lipid phosphatase SHIP2 improve muscle insulin Endocrinology 2015;11(2):581–90.