Insulin resistance in type 1 diabetes mellitus Kirti Kaul, Maria Apostolopoulou, Michael Roden PII: DOI: Reference:

S0026-0495(15)00256-5 doi: 10.1016/j.metabol.2015.09.002 YMETA 53282

To appear in:

Metabolism

Received date: Accepted date:

13 July 2015 3 September 2015

Please cite this article as: Kaul Kirti, Apostolopoulou Maria, Roden Michael, Insulin resistance in type 1 diabetes mellitus, Metabolism (2015), doi: 10.1016/j.metabol.2015.09.002

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Insulin resistance in type 1 diabetes mellitus

Authors:

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KirtiKaula,b,*, Maria Apostolopoulou a,b,*, Michael Rodena,b,c**

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Affiliations:

Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes

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Research at Heinrich-Heine University Düsseldorf, Germany;bGerman Center of Diabetes

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Research Partner, Düsseldorf, Germany; cDepartment of Endocrinology and Diabetology,

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Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany

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* both authors equally contributed to this work

**Corresponding author: Dr. Michael Roden

Department of Endocrinology and Diabetology Medical Faculty, Heinrich-Heine University Institute for Clinical Diabetology, German Diabetes Center c/o Auf`m Hennekamp 65 D-40225 Düsseldorf, Germany Phone: +49-211-3382-201 1

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E-mail: [email protected]

Keywords:

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Type 1 diabetes mellitus; insulin sensitivity; glucotoxicity; lipotoxicity; mitochondria;

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inflammation

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Words:4252/5000; Abstract: 192/200; References: 98/100; Tables + Figures: 4

Abbreviations: MRS, magnetic resonance spectroscopy; AMPK, 5´AMP activated protein kinase;

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AGE, advanced glycation endproduct; ATP, adenosine triphosphate; bEGP, basal endogenous

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glucose production; DAG, diacylglycerol; FDR, first degree relative; FFA, free fatty acids; GIR, glucose infusion rate; HEC, hyperinsulinemic-euglycemic clamp iEGP, insulin mediated

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suppression of EGP; IMCL, intramyocellular lipids; IRS, insulin receptor substrate; MCR, metabolic clearance rate; JNK, c-Jun-N terminal kinase pathway; MAPK, mitogen activated protein kinase; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B-cells; PI3KAKT, phosphatidylinositol-4,5-bisphosphate 3-kinase-protein kinase B; PKC, protein kinase C; Ra, glucose appearance rate; RAGE, receptor for advanced glycation end product; Rd, glucose disposal rate; ROS, reactive oxygen species; SREBP, sterol regulatory element binding protein; STZ, streptozocin; T1D, type 1 diabetes; T2D, type 2 diabetes

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ACCEPTED MANUSCRIPT Abstract For long the presence of insulin resistancein type 1diabetes has been questioned. Detailed

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metabolic analyses revealed12-61% and up to 20% lower whole-body (skeletal muscle)and hepatic insulin sensitivity in type 1 diabetes, depending on the population studied. Type 1

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diabetes patients feature impaired muscle adenosine triphosphate (ATP) synthesis and enhanced oxidative stress, predominantly relating to hyperglycemia. They may also exhibit abnormal

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fasting and postprandial glycogen metabolism in liver, while the role of hepatic energy

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metabolism for insulin resistance remains uncertain. Recent rodent studies point to tissuespecificdifferences in the mechanisms underlying insulin resistance.In non-obese diabetic

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mice,increasedlipid availability contributesto muscle insulin resistance via diacylglycerol/protein kinase C isoforms. Furthermore, humans with type 1 diabetes respond to lifestyle modifications

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or metforminby 20-60% increased whole-body insulin sensitivity, likely through improvement in

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bothglycemic control and oxidative phosphorylation.Intensive insulin treatment and islet transplantation also increase but fail to completely restore whole-body and hepatic insulin

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sensitivity. In conclusion, insulin resistance is a feature of type 1 diabetes, but more controlled trials are needed toaddress its contribution to disease progression, which might help tooptimize treatment andreducecomorbidities.

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Background

Type 1 diabetes mellitus (T1D) results from primary loss of β-cell mass due to complex

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autoimmune processes with consecutive insulin deficiency, while type 2 diabetes (T2D) arises

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from impaired insulin action, also termed insulin resistance, along with inadequate β-cell function

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and insulin secretion [1]. According to this paradigm, it is counterintuitive that T1D patients should be insulin resistant. Nevertheless, clinical and experimental evidence suggeststhat insulin

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resistance can indeed be present in T1D. Previously, chronic hyperglycemiawas considered the

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exclusive contributor to insulin resistance in patients with long-standing, poorly-controlled T1D [2]. More recent studies highlight a more complex nature of insulin resistance in T1D. The

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evidence of insulin resistance in T1D has been particularly reviewed in the context of vascular comorbidities [2-5].Here, we aim to summarize the current literature addressing tissue-specific

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insulin resistance in T1D and to analyze possible contributors to insulin resistance.

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The relevant literature was retrieved by searching for the terms ―hepatic and whole-body insulin resistance‖, ―hepatic glucose flux‖, ―insulin resistance in animal models‖, ―energy metabolism‖,

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―mechanisms of insulin resistance‖, ―insulin treatment‖, ―metformin‖, ―insulin sensitizers‖, ―glucotoxicity‖, ―lipotoxicity‖, ―diet‖, ―exercise ‖, ―islet transplant‖ and ―mitochondria‖ related to T1Dfrom 1982 to February 2015 in PubMed. Further references were identified byanalyzing the retrieved publications and by the authors´ personal knowledge. 2.

Definition and measurement of insulin resistance

Impairment of insulin action comprises reduced insulin responsiveness and insulin sensitivity. In vitro, a lower maximal effect of insulin reflects decreased insulin responsiveness, whereas lower insulin sensitivity isdefined by a higher insulin concentration eliciting the maximal response to insulin, i.e. a right shift of the dose response curve [6]. In vivo, the gold-standard 4

ACCEPTED MANUSCRIPT hyperinsulinemic-euglycemic clamptest (HEC) would theoretically allow for separation of insulin responsiveness from sensitivity. However, most clinical-experimental studies employ the HEC

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with one signal insulin dose rather than across a broad range of insulin doses so that insulin

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resistance generally reflects a reduction of both features of insulin action. Nevertheless, HEC is optimal for assessing glucose fluxes in T1D, while fasting indices of glucose tolerance tests, as

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frequently used in T2D patients, rely on insulin secretion and therefore are not applicable due to

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the insulin deficiency in T1D patients [2,6]. When combined with dilution techniques using isotopically labeled glucose tracers, the HEC provides information about glucose fluxes and

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tissue-specific insulin sensitivity in vivo. In the absence of exogenous insulin and in the presence of normoglycemia, therate of glucose disappearance (Rd) equals the rate of glucose appearance

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(Ra), which then representsbasal (fasting) endogenous glucose production (bEGP). In

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thepresence of supraphysiological insulin concentrations, the exogenous variable input of glucose required to achieve euglycemiaat steady state is given by the glucose infusion rate (GIR) and Rd.

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Under these hyperinsulinemic conditions,insulin-mediated endogenous glucose production

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(iEGP) is suppressed.Lower response to insulin results in insufficient suppression of iEGP and lower Rd[6].In addition, adipose tissue insulin resistance can bederivedfrom impaired insulinmediated suppression of lipolysis, reflected by impaired lowering of circulating free fatty acids (FFA) or more precisely by using lipid tracers [7,8]. 3. Key mechanisms underlying insulin resistance Insulin resistance can be a (patho)physiological phenomenon occurring as transient adaptation to puberty, dehydration, infections, several drugs, and smoking [31,32]. On the other hand, common insulin resistance as observed in obesity and T2D results from a complex interaction of environmental and inherited factors and progresses chronically. 5

ACCEPTED MANUSCRIPT At the cellular level, stimulation by insulin activates tyrosine kinase of the insulin receptor, which stimulates insulin receptor substrate (IRS) phosphorylation followed by activation of 3-kinase-protein

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B(PI3K-AKT).

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phosphatidylinositol-4,5-bisphosphate

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mechanisms can induce insulin resistance by interfering with the insulin signaling cascade, i.e. elevated blood glucose, lipids and amino acids, oxidative and endoplasmic reticulum stress,

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systemic and cellular inflammation and inherited variations in the signaling molecules (Figure 1).

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Hyperglycemia lowers insulin signaling through different mechanisms including higher glucose flux to the hexosamine pathway, activation of stress-regulated pathways such as c-Jun-N terminal

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kinase pathway (JNK), protein kinase C (PKCs), preferentially PKCβ activation and oxidative

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stress driven pathways [9]. Hyperglycemia is also known to increase the formation and accumulation of advanced glycation end products (AGE), which contribute to inflammatory

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pathways and may also directly interfere with insulin signaling and hepatic energy metabolism

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[10-12]. Short-term high-dose glucose infusion in rats reduced hepatic and whole-body insulin sensitivity,which associated with doubling of muscle diacylglycerol (DAG) and malonyl-

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CoAalong with a 50% decrease in AMPK activity [13]. This highlights an overlap between the downstream effects of hyperglycemia and higher accumulation of toxic lipid metabolites, in line with the concept of glucolipotoxicity [14]. Excessive availability of lipids and amino acids are known to interfere with the insulin signaling cascade. Lipid infusion studies resulting in elevated circulating FFA, provide important insight into the acute sequence of events, by which certain muscle C18-DAGcause translocation of PKCθ with subsequent inhibitory serine phosphorylation of IRS-1 and reduction of insulinmediated glucose transport/phosphorylation followed by impaired glycogen synthesis in skeletal muscle[15,16].Short-termelevation of circulating amino acids also results in lower insulin6

ACCEPTED MANUSCRIPT mediated muscle glucose transport/phosphorylation along withimpaired hepatic glycogen synthesis [17]. This is likely due to amino acid-induced activation of the rapamycin-sensitive

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mTOR/serine-6-kinase-1 pathway, which causes inhibitory serine phosphorylation of IRS-1 [18]. Other mechanisms, particularly cellular inflammatory pathways resulting innuclear factor kappa-

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light-chain-enhancer of activated B cells (NF-κB) transcription and JNK activation can contribute to chronic insulin resistance. Circulating cytokines, but also FFA, can activate JNK, which

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directly inhibits phosphorylationof IRS-1 and has been associated with insulin resistance and

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obesity [19]. Other abnormalities of insulin signaling include the loss of activation of the PI3K pathway, mitogen activated protein kinase (MAPK) pathway, and activation of transcription

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factors such as sterol regulatory element binding protein (SREBP), which contribute to cell growth, protein synthesis and mitochondrial function [20,21].

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Also rare inherited variations in the insulinsignaling cascade can induce insulin resistance, e.g. by

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modulating the insulin-to-insulin receptor interaction. The G972R variant on IRS-1 has been linked to T1D in the European population [22]. At the molecular level conformational changes

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due to this natural variance in IRS-1, carriers of the G972R variant exhibit reduced phosphorylation of IRS-1 along with simultaneous inhibition of insulin receptor kinase activity as well as impairing insulin secretion [22,23]. In T2D, abnormal mitochondrial functionmay be causally or consequently associated withinsulin resistance, and is thought to contribute to disease progression [24]. Aside from impaired oxidative glucose and lipid metabolism, generation of reactive oxygen species (ROS) and oxidative stress seems to play an important role in modulating and ultimately inhibiting insulin signaling.In addition, ROS-mediated damage to cellular proteins, lipids and nucleic acids could result

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ACCEPTED MANUSCRIPT response[19,25].Recent studies also suggest that the unfolded protein response activates the pattern recognition receptors of the immune system, resulting in an autoimmune response [26].

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Finally, increased serum insulin concentration, either transiently during the ―honeymoon phase‖ or resultingfrom chronic insulin treatment, has also been considered to contribute to insulin

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resistance. Hyperinsulinemia appears to increase whole-body and hepatic insulin resistance in rodent model of T1D via abnormal mitochondrial function and prolonged oxidative stress [27].

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Epidemiological studies in humans suggest that high iatrogenic hyperinsulinemiamay contribute

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to insulin resistance in T1D and subsequently to associated complications[28, 29].While this is further supported by the observation that hyperinsulinemia blunts the response ofwhole-body

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insulin sensitivityto exercising in T1D humans [30], a direct role of circulating insulin in the development of insulin resistance is still uncertain.

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4. Hypotheses linking insulin resistance and type 1 diabetes

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Over the years, a few hypotheses proposed a link between insulin resistance and the development

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of T1D. The ―Double Diabetes‖ hypothesis, formulated in 2001, states that patients with predominant metabolic dysregulation and a less dominant autoimmune aberration represent the overlapping population of T1D autoantibody positive individuals with lower insulin sensitivity [33]. Insulin resistance is thought to arise from obesity, lifestyle as well as genetic background of the patient. While the genetics of these individuals with double diabetes is similar to those with T1D, they show lower frequency for major histocompatibility complex (MHC) genes and greater association with genes contributing to the risk of T2D [24,34-37]. At the molecular level, double diabetes would be characterized by the presence of obesity linked cytokine expression, which in turn leads to a more aggressive β-cell apoptosis [36]. This concept is further supported by the observation that T1D patients show an appreciably high family history of T2D [37, 2]. 8

ACCEPTED MANUSCRIPT The ―Accelerator‖ hypothesis also considers obesity-driven development of insulin resistance as the central feature of both T1D and T2D[38]. This concept is based on a number of cross-

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with more aggressive progression of the autoimmune process [34].

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sectional studies reporting thathigher body weight at the time of diagnosis of T1D is associated

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Finally, concepts such as the ―Fertile Field‖ hypothesis suggest that abnormal metabolic function compromises β-cells, making them more susceptible to autoimmune phenomena triggered

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byenvironmental factors such as microbial/viral infection [39].

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5. Studies on hepatic insulin resistance in T1D

In hepatocytes, decreased insulin response results in lower glycogen synthesis and lower

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suppression of gluconeogenesis thus enhancing glucose output, i.e. EGP. Monitoring of 13

C magnetic resonance spectroscopy (MRS)in poorly-

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postprandial hepatic glycogen fluxes by

controlled patients with T1Drevealed lower net rates of glycogen synthesis after a meal [40-42]. 13

C MRS with ingestion of2H2O provides for measuring gluconeogenesis and

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Combining

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administration of [1-13C]glucose and acetaminophen allows for sampling the hepatic UDPglucose pool. Employing these techniques, we found excessive gluconeogenesis increasing the indirect (gluconeogenic) pathway of glycogen synthesis as well as elevated glycogenolysis leading to futile glycogen cycling in poorly-controlled T1D [42]. These abnormalities can result in prolonged hyperglycemia after a meal and higher risk of hypoglycemia in the fasted state [40]. Figure 2A compares rates of postprandial hepatic glycogen synthesis in patients with long standing T1D to those of healthy humans and patients with T2D. Net rates of glycogen synthesis partially improvethrough intensive acute glycemic control by insulin and normalizewith longterm near-normoglycemic control in T1D. While near-normoglycemic control also decreases the elevated rates of glycogen cycling, which is the simultaneous synthesis and breakdown of 9

ACCEPTED MANUSCRIPT glycogen,the contribution of theindirect gluconeogenic pathway to glycogen synthesis remains higher suggestingthat intrinsic abnormalities or hepatic insulin resistance may be present in T1D

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independent of glycemic control [41]. 13

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During hyperglycemic-hyperinsulinemic clamps combined with

C MRS, [1-13C]glucose

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acetaminophen as well as phenylacetate to sample the hepatic glutamine pool, the contribution of gluconeogenesis to glycogen synthesis was also found to be increased, while that of pyruvate

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oxidation to the tricaboxylic acid cycle was decreased in poorly controlled T1D [41].

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The fewclamp studies employing isotope dilution to monitorEGP at baseline and during hyperinsulinemia, revealed inconsistent results in T1D.Table 1 summarizes data on hepatic

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insulin sensitivity in studies usingHEC combined with isotope dilution (47, 48, 52, 61, 49, 7). Three studies (47,48,52) reported elevated basal EGP in T1D patients, whereas one study (49)

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reported comparable basal EGPin8 patients with T1D on continuous subcutaneous insulin

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infusion and 8 healthy controls. Insulin-mediated EGP suppression was impaired in two studies (57,72), but complete in two other studies (48, 7). The discrepancybetween the studies may result

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from differences in insulin dosing before the study, clamp insulin infusion rates, reported partial T1D remission in some patients and last but not leastvariable glucometabolic control. As none of these studies used somatostatin infusions,endogenous insulin releasein the control persons may have led to variable differences in EGP compared to T1D patients. Similar to obesity and T2D [49,50]circulating and hepatic lipidscould contribute to insulin resistance through activation of isoforms of PKCs in T1D,Evidence for augmented hepatic lipid storagehas been reported in some studies, while other studies foundlower hepatic fat content in both lean and obese T1D patients [51-53]. This difference may relate to cohort features such as body fat mass or family history of T2D. Lower hepatic lipids may also beattributed to lower 10

ACCEPTED MANUSCRIPT insulin-stimulated hepatic lipogenesis due to insufficient portalinsulinemia in the case of peripheral insulin supplementation in T1D.

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Studies in mice allowed elucidatingmechanisms of hepatic insulin sensitivity and oxidative capacity in more detail. Non-obese mice (NOD) mice spontaneously develop autoimmune

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diabetes and can serve as a model for human T1D [54]. These mice exhibit hepatic insulin resistance with increased membrane translocation of PKCε and impaired insulin-stimulated AKT

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phosphorylation suggesting a role of lipotoxicity, along with a trend towards higher hepatic

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oxidative capacity even before diabetes manifestation. At the onset of disease, characterized by both hyperinsulinemia and elevated FFA, NOD mice havemarkedly increased oxidative capacity,

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possibly explaining their lower hepatic triglyceride content. Despite insulin treatment, hepatic oxidative capacity declines in these mice with prolonged disease duration.Streptozotocin (STZ)-

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treated and thereby insulin-deficient rats similarly show abnormal liver mitochondrial function,

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although hepatic insulin sensitivity is not available in this model[55]. InAkita mice, another model of insulinopenic diabetes,expression of hepatic oxidative phosphorylation and fatty acid

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oxidation proteins was also higher despiteunchanged mitochondrial density andrespiration, butagain no data on hepatic insulin sensitivity were reported[56]Collectively these abnormalities can give rise to lipid peroxidation and ROS-associated apoptosis [54-56], which may lead to insulin resistance by mechanisms linked to oxidative stress. While T1D is essentially understood as an autoimmune disease, T1D may share somesimilarities with T2D, particularly regarding systemic and intracellular inflammation [57]. Of note,NOD mice have increasedcirculating concentrations of the hepatokine,fetuin, which mediates FFA binding to toll-like receptors and thereby activates inflammatory pathways [57, 58]. These mice also present with hepatic JNK activation even before the onset of diabetes. While this suggests an 11

ACCEPTED MANUSCRIPT effect occurring independently of hyperglycemia and hyperlipidemia, JNK activation may likely result from hepatic oxidative stress.

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6. Studies on whole-body insulin resistance in T1D 6.1. Muscle insulin resistance

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In myocytes, impaired insulin action primarily results in lower glucose uptake with subsequent

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reduction of glycogen synthesis. Table 1 summarizes data on whole-body (peripheral), i.e. mainly skeletal muscle, insulin sensitivity during HEC (47, 52, 61, 49, 74, 26, 46, 64, 7). Data on glucose

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disposal rates in patients with poorly and well controlled T1D in comparison to healthy controls and patients with T2D are depicted in Figure 2 B.

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While iEGP suppression in metabolically well-controlled T1D can be comparable to healthy

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humans, whole-body insulin sensitivity generally remains lower in T1D patients despite adequate or even higher insulin availability [45, 49].Poorly-controlled T1D patients hadlower whole-body

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glucose disposal compared to matched controls even in the presence of lower intrahepatic fat

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content, suggesting that hyperglycemia underlies whole-body insulin resistance (7, 52). But also well-controlled T1D patients with a diabetes duration exceeding 10 years showed lower wholebody glucose utilization,even after adjustment for age, sex, BMI and fasting glucose (26,46). These studies did not find an association of muscle insulin resistance with glycemic control, suggesting a role of peripheral hyperinsulinemia rather than hyperglycemia in the development of insulin resistance T1D. However, at thelow insulin infusion rate (4mU/m2/min) of these 3-step insulin clamps,glucose concentrations rose in the patients, which limits the comparability of the data with those of healthy controls. Another study examined whole-bodyinsulin sensitivity in newly diagnosed T1D patients when ketoacidosis had disappeared and again during insulin therapy. The initial 35-% reduction of insulin sensitivity reversed after 3-m insulin therapy. Of 12

ACCEPTED MANUSCRIPT note, five patients had a normal C-peptide secretion at this time, suggesting clinical remission of diabetes. At the cellular level, lower expression of insulin receptors and GLUT4 was found at

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least in obese T1D patients [59,60]. Furthermore, higher glycolytic flux along with lower oxidative capacity,similar to T2D, has been

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also observed in patients with T1D [61] and some other studiesprovided evidence for abnormal mitochondrial function in insulin resistant T1D [62, 63, 64]. A31P MRSstudy found thateven

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well-controlled T1D patients feature prolongedphosphocreatine (PCr)recovery compared

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withmatched controls suggesting impaired muscle (sub)maximal oxidative capacity(62). Delayed ADP-to-ATP conversion times, associated with insulin resistance, but not with glycemic control

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in T1D (63).This study, however, did not include data on insulin sensitivity. In another study (64), well-controlled T1D patients exhibited 50% lower whole-body glucose disposal along with

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25% lower flux through ATP synthase. Insulin-stimulated fATP correlated positively with whole-

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body insulin sensitivity. While these data might suggest a primary role of abnormal mitochondrial function in the development of insulin resistance, the finding of a tight correlation

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between glycemic control and insulin-stimulated ATP synthase flux does not favor this hypothesis (64).Other studies examined the role of oxidative stress profile in blood samples, as a surrogate of abnormal mitochondrial function (65,66), but failed to provide data on insulin sensitivity. Adolescents with poorly controlled T1D showed depletion of blood glutathione and cysteine, indicating reduced antioxidant capacity (66). But even T1D with short disease duration and good glycemic control exhibited reduced antioxidant capacity along with increased oxidative stress and lipid peroxidation(65). Only few studies have examined the impact of innate immunity and inflammatory pathways in the progression of muscle insulin resistance in T1D and yielded controversial results, e.g. for toll13

ACCEPTED MANUSCRIPT like receptors and interleukin-1β [67]. In insulin-resistant T1D patients without macrovascular complications, circulating C-reactive protein (CRP) was higherand correlated positively with

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glycemic control and parameters of central obesity [68]. One might hypothesize that also

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autoimmune reactions might drive insulin resistance. However, islet autoantibody-positive patients, originally diagnosed as T2D, have higher insulin sensitivity than autoantibody-negative

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patients[70], confirming that autoimmunity per se may not lead to insulin resistance, whereas

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insulin resistance appears to influence the intensity of autoimmune responses [57,70,71].

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6.2. Adipose insulin resistance

T1D patients may also exhibit insulin resistance at the level of adipose tissue, as theymay have

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higher circulating FFA and glycerol levels during low-dose insulin (8 mU/m2/min) HEC, indicatingimpaired insulin-mediated suppression of lipolysis (8, 7, 64, 26, 74, 49; Table 1).

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Lower FFA suppression was found in poorly (7) and well-controlled T1D (26, 49). The higher

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availability of FFA and glycerolwill in turn contribute to glycogen synthesis by the indirect pathway and thereby reduce whole-body glucose uptake [7, 26]. Moreover, higher circulating

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FFA will promote ectopic lipid deposition as IMCL, which correlates negatively with indices of insulin sensitivity also in T1D [26, 61]. Of note, glucose metabolic clearance rate, which is defined as glucose disposal normalized to circulating glucose concentration, and IMCL were comparable between T1D and T2D patients and insulin resistant first degree relatives (FDR) of T2D [61]. The finding thatpoorly-controlled T1D patients have higher IMCL along with lower glucose metabolic clearance ratethan well-controlled T1D patients suggest thathyperglycemia also fosters ectopic fat deposition.

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ACCEPTED MANUSCRIPT 7. Interventions addressing insulin sensitivity in T1D Interventions that are typically associated with improvement in insulin sensitivity in T2D have

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also proven to be beneficial to patients with T1D. Diet and exercise interventions in T1D have revealed valuable information in terms of improvement in metabolic factors, although a majority

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of these investigations are not directed at the assessment of direct changes in insulin sensitivity [4, 5]. Table 2 provides a summary of findings from studies reporting glucose fluxes in vivo at

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baseline as well as post-intervention.

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Firstly, diet appears to improve whole-body insulin sensitivity, despite unchanged body weight and glycemic control [72,73]. Anisocaloriclow fatdiet appears to improve whole-body insulin

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sensitivity (72), however, substantial loss of body fat after one-weekfast was linked with a transient increase in insulin resistance in T1D [73]. This waslinked tolower glucose oxidation and

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greater fat oxidation.A study comparinglean T1D and T2D individuals of Asian origin revealed

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greater insulin resistance in T2D patients and suggestedthat adipocyte fatty acid binding protein

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is associated with Rd, independent of BMI [74]. The effect of exercise on glucose metabolism of patients with T1D has been also examined in several studies [63, 75-80]. One acute bout of moderate and high intensity exercise resulted in increased rates of hepatic glucose production, mainly attributed to increased gluconeogenesis. [75]. Longer-term exercise interventions support evidence of 20-60% improvement inwhole-body insulin sensitivity, with moderate to low changes in hepatic insulin sensitivity [76-78]. A 6-weeks cycling training program, performed four times weekly,resulted in an increase in a 60-% risein GIR and 6-% reduction of daily insulin needs, but unchanged HbA1c. A12-weeks aerobic training,performed three times weekly, also led to improved insulin sensitivity despite unchanged body weight and glycemic control.After 16 weeks of aerobic exercise training, whole-body 15

ACCEPTED MANUSCRIPT insulin sensitivity rose by 23%, which was partly attributed to an increase in succinate dehydrogenase activity and normalization of glycogen synthase activity [77]. Six weeks of

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physical training in patients with T1D and age- and BMI- matched controls also showed a

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tendency to glycogen synthase activity normalization, along with a decrease in daily insulin requirements but unaffected insulin receptor function (79). In a small study, T1D patients with

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long standing well-controlled diabetes showed a shift to lipid oxidation in response to exercise,

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similar to healthy control participants [80]. Exercise intervention studies in lean and young T1D patients also indicate a lower rate of oxidative phosphorylation along with delayed ADP

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recovery[63]. Taken together, these observations support the potentialrole of mitochondrial function in whole-bodyinsulin resistance, which is subsequently improved by exercise without

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affecting glycemic control.

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Intensive glycemic control by variable subcutaneous insulin infusion has been suggested to

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improve insulin response in T1D patients by reducing glucotoxicity and results in reduction in insulin requirements and hepatic glucose production [81, 82].A 6-weeks continuous subcutaneous

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insulin infusion pump treatment improvedwhole-body insulin sensitivity by 27%, decreased bEGP and thereby improved glucometabolic control in T1D patients with disease duration of more than 8 years.

Intervention studies using metformin as add-on to insulin therapyrevealed an approximately 40% improvement in whole-body insulin resistance in T1D, mostly despite unchanged glycemic control [83-87]. The metformin (500-850 mg daily) add-on treatmentfor 3 months decreased insulin requirementsand increaseswhole-body glucose uptake without affecting glycemic control in obese T1D[83]. Of note, only one double-blinded placebo controlled metformin study showed

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ACCEPTED MANUSCRIPT improved muscle insulin sensitivity with a parallel decrease in HbA1c in adolescents with poorly controlled T1D (86).

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After 4 weeks of treatment with the growth hormone antagonist, pegvisomant, moderately improved GIR and hepatic insulin sensitivity and decreased IMCL in T1D patients[88]. The

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concomitant decrease in FFA levels during HEC implies as an underlying mechanism thesuppression of lipolysis, which is induced by growth hormone.

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Furthermore,techniques to restore insulin secretion by pancreatic islet or combined kidney-

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pancreas transplantation showratherimprovements inwhole-body insulin sensitivity, than infasting hepatic insulin sensitivity [89-91]. However, unimproved insulin sensitivityof transplant

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recipients may be due to chronic immunosuppressive therapy (91). Nevertheless, combined kidney-pancreas transplantation showed appreciable increases in hepatic as well as whole-body

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insulin sensitivity during HEC along with improved FFA suppression and decreased

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glucagon,[91].

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Finally, prospective observation and prevention studies might help to better understand insulin resistance in the course of the disease. The diabetes prevention trial (DPT-1) detected abnormal oral glucose tolerance in FDR of T1D patients as early as 2 years prior to diabetes onset along with consecutive deterioration of the first-phase insulin response[94,95]. Unfortunately,wholebody and hepatic insulin sensitivity werenot assessed in detail in such individuals at high risk of developing T1D. Also, the efficacy of lifestyle preventionto improve insulin action and to delay the onset of T1D remains largely unknown, but could reducethe cardiometabolic risk in these patients [4,5].

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ACCEPTED MANUSCRIPT 8. Conclusion There is compelling evidence that insulin resistance in T1D can be present and thatnot only

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hyperglycemia but also other mechanisms are responsible for tissue-specific discordance in its development.Neverthelessthe precise role of insulin resistance in the development and

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progression of T1D is still incompletely understood.

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9. Outlook

A more comprehensive, combined investigation of hepatic and whole-body insulin sensitivity,

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and the possible underlying mechanisms in persons with or at high risk of T1D is needed to shed light on the sequence of events and risk factors that contribute to the metabolic abnormalities in

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T1D aside from insulin deficiency. Further addressing of the inherited and acquired associations

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between T1D and T2D, would help establish the polygenic and complex nature of T1D and

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ultimately improve prevention and treatment of diabetes.

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ACCEPTED MANUSCRIPT Acknowledgments The authors´ work is supported by the Ministry of Science and Research of the State of North

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Rhine-Westphalia (MIWF NRW), the German Federal Ministry of Health (BMG) and by grants

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of the Federal Ministry for Research (BMBF) to the German Center for Diabetes Research (DZD e.V.), the Helmholtz Alliance with Universities (Imaging and Curing Environmental Metabolic

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Diseases, ICEMED), the German Research Foundation (DFG; SFB 1116, B05) and the

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Schmutzler Stiftung, Germany. Conflict of interest

There are no potential conflicts of interest relevant to this article.

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Author contributions

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K.K., M.A and M.R. co-wrote the review article.

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ACCEPTED MANUSCRIPT References [1] American Diabetes Association. Standards of medical care in diabetes—2015. Diabetes Care

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Diabetes Care 2015;38(Suppl. 1):S1–S2

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[2] Cleland SJ, Fisher BM, Colhoun HM, Sattar N, Petrie JR. Insulin resistance in type 1 diabetes: what is ‗double diabetes‘ and what are the risks? Diabetologia 2013;56:1462-70.

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[3] Krochik AG, Botto M, Bravo M, Hepner M, Frontroth JP, Miranda M, et al. Association

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ACCEPTED MANUSCRIPT Figure Legends Figure 1

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This flow chart summarizes current concepts for the understanding of insulin resistance in T1D.A main proposed mechanism is the inhibition of insulin signaling, as a result of chronic

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hyperglycemia, increased plasma FFA and aminoacids and inflammatory processes. JNK: c-JunN terminal kinase pathway, PKC: protein kinase C activity AGE: advanced glycation end

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products, FFA: free fatty acids, IRS-1: insulin receptor substrate 1 ROS:reactive oxygen species, DAG: diacylglycerol Figure 2

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This figure summarizes glycogen synthesis (Vsyn) as assessed by several studies, expressed as a percentage of glycogen synthesis in control individuals, where 100% equals 0.4 mmol/l liver/min

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approximately (A) [41,43,44, 97, 98] and data on glucose disposal rates in studies where hyperinsulinemic-euglycemic clamps were performed(7, 38, 49, 74) (B). T1Dp: T1D patients

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with poorly controlled glycemic parameters, T1Dc: T1D patients with well controlled blood

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glucose for a period of a year, Con: Healthy volunteers

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ACCEPTED MANUSCRIPT Table 1 Tissue-specific insulin sensitivityas assessed with hyperinsulinemic-euglycemic clamps in patients with T1D compared to healthy controls. Participants HbA1c % Methods

Hepatic IS

Whole-

Adipose IS

T

Author

(mmol/L)a

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body

al. [47]

HEC + 3H- ↔ iEGP

n. r.

36 Con

Yki-Järvinen

14 T1D vs.

et al. [48]

14 Con

14.3 (133)

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DeFronzo et 11 T1D vs.

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(muscle) IS

32

%↓ n.r.

glucose

GIR

infusion

61%↓ Rd

HEC + 3H-

n.r.

n.r.

HEC + 1H 20%↓ iEGP

34%↓

n.r.

MRS

MCR

↔ iEGP

ED

glucose

infusion

19 Con

CE

al. [52]

18 T1D vs.

al. [61]

22

8.6 (72)

AC

Perseghin et 15 Con

8.7 (72)

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Perseghin et 19 T1D vs.

%



HEC + 3H- iEGP

n.r. 30%↓ GIR

glucose infusion

Donga et al. 8 T1D vs. [49]

7.4 (57)

HEC + 3H- 15%↓ iEGP

38%↓ Rd

glucose

8 Con

158%↑

FFA

levels

infusion Hsu

et

[74] Schauer

al. 10 T1D vs.

6.9 (52)

HEC

n.r.

12%↓ Rd

FFA

suppression

11 Con et 40 T1D vs.



7.5 (59)

3-step

n.r.

50%↓ GIR

100%↑ FFA and

32

ACCEPTED MANUSCRIPT

Bergman et 25 T1D vs.

7.7 (61)

8 T1D vs.

6.8 (51)

MRS et 10 T1D vs.

HEC + 2H- completely

10 (86)

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al. [7]

n.r HEC + 1P

8 Con

et al. [64] Heptulla

45%↓ Rd

n.r.



HEC

25 Con

Kacerovsky

3-step

glucose

6 Con

50%↓ GIR

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al. [46]

glycerol levelsb

HEC

T

47 Con

SC

al. [26]

39%↓ Rd

suppressed

3-step

ED

al. [8]

7.7 (61)

HEC

20%↓

FFA

40%↓

glycerol

suppression n.r.

50%↓

glycerol

suppressionb 25%↓palmitate suppressionb ↔c

AC

CE

PT

25 Con

n.r.

suppression

suppression

infusion

Bergman et 25 T1D vs.

FFA

These observations are given as percent difference related to the corresponding control group. a

HbA1c reported in patients with T1D only ; bat lower insulin doses of 4 and 8 mU/m2/min; c No

difference in glycerol or palmitate supression at 40 mU/m2/min insulin; ↓ lower vs Con; ↑ higher vs Con; ↔ no difference vs Con. 1

H MRS, 1H magnetic resonance spectroscopy; 13C MRS, 13C magnetic resonance spectroscopy;

3-step HEC, hyperinsulinemic-euglycemic clamp at 4-8-40 mU/m2/min; bEGP, basal endogenous glucose production; Rd, basal glucose appearance rate; Rd, basal glucose disposal rate; Con, control participant; FFA, free fatty acids; GIR, glucose infusion rate; HEC, 33

ACCEPTED MANUSCRIPT hyperinsulinemic-euglycemic clamp; iEGP, insulin stimulated supression of EGP under clamp conditions; IS, insulin sensitivity; MCR, metabolic clearance rate; n.r., not reported; Ra, glucose

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appearance/production rate under clamp conditions; Rd, glucose disposal rate under clamp

AC

CE

PT

ED

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SC

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conditions; T1D, type 1 diabetes patient

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ACCEPTED MANUSCRIPT Table 2 Impact of interventions on tissue-specific insulin resistance, glycemic control and insulin dosage in type 1 diabetes (T1D). Total

T1

HbA1c

Hepati

dose/durat

durati

D

%

c IS

ion

on (d)

(n)

(mmol/m ol)

al.

vs. Low fat diet

Musil

et Fasting +

al. [73]

Low-calorie diet

Fasting: 7 d 30 Low-

8.5 (70)

14

7.9 (63)

n.r.

body

27%↑

n.r.

30%↓



Järvinen

(Spiroergome

et al. [76]

try)

Wallberg-

Exercise

1 h/d;

Henriksso

(Aerobic

3 d/w

42

in dose





10%↓ 0.11a ↓

MCR 7

8.6 (70)



60%↑

n.r.

3c↓



n.r.



n.r.

GIR

4 d/w

AC

1c

Rdf

21d

1 h/d;

Insul

Rd

↔ RdLC

Exercise

HbA

IS

calorie diet:

Yki-

et

10

ED

[72]

n

168

PT

et

Standard

CE

k

Low-fat diet

MA NU

Rosenfalc

Whole-

T

e

Daily

RI P

Treatment

SC

Referenc

112

10

10.4 (90)

n.r.

20%↑ GIR

al. training)

[77] Landt al. [78]

et Exercise (Spiroergome

45 min/d; 3 d/w

84

9

12 (108)

n.r.

23%↑ Rd

try)

35

ACCEPTED MANUSCRIPT Petersen

Exercise

50

min/d 1

et al. [75]

(Aerobic

(MO)

training)

50

5

7.9 (63)

100%↑

n.r.

n.r.

n.r.

GlyLys min/d

T

MO

350%↑

RI P

(HI)

Gly

SCII

26 U/day

42

Järvinen et al. [81] Lager

et SCII

38.3 U/day

8

Gin et al. Metformin

ED

al. [82] 850 mg/day 7

Metformin

500 mg/d; 84 w1

10.5 (91)

7

10

9.7 (83)

9.95 (85)

58%↓

27%↑

20%↓ 10c↓

30%↑

20%↓ n.r.

bEGP

n.r.

Rd n.r.

18%↑





GIR 26

9.5 (80)

n.r.

45%↑

10%↓

Rdb

CE

et al. [86]

PT

[84] Sarnblad

10

MA NU

Yki-

SC

LysHI

AC

1000 mg/d; w 2-4 2000 mg/d; w 5-12

Moon

et Metformin

al. [83] Thankam ony et al. [88]

500-850

84

16

9.4 (79)

n.r.

mg/d Pegvisomant

10 mg/d

36%↑



5.1c↓

n.r.

0.1a↓

GIR 28

10

8.26 (67)

25%↑

↔ Rd

iEGP

41%↑ GIR

36

ACCEPTED MANUSCRIPT Rickels et Islet al. [89]

Surgery

-

12

7.1 (54)

38%↑

n.r.

transplant

Rd

23%↓ 0.46a ↓

T

50%↑G

Rickels et Islet

-

12

transplantatio n Surgery

-

pancreas transplantatio

8.9 (74)

24%↑ GIR

30%↓

70%↑

bEGP

GIR

20%↓ 0.42a ↓

35%↓ 40c↓

50%↓ iEGP

ED

n

15

MA NU

Luzi et al. Kidney-

PT

Changes in parameters are reported as % change of baseline.

CE

Rdb Glucose disposal rate normalised to insulin concentration under clamp conditions; aInsulin requirement in U/kg/day; cInsulin requirement in U/day; ↓ reduced vs baseline; ↑ higher vs baseline; ↔ no different vs baseline.

AC

[91]

7.0 (53)

SC

al. [90]

Surgery

RI P

IR

bEGP, basal endogenous glucose production; Con, control person; d, day; Rd, glucose disposal rate; Rdf, glucose disposal rate under fasting conditions; RdLC, glucose disposal rate under low calorie diet conditions; GIR, glucose infusion rate; Gly Lys, glycogenolysis; VSyn, net hepatic glycogen synthesis; h, hour; HI, High intensity exercise at 70% VO 2max; iEGP, insulin stimulated suppression of EGP under clamp conditions; IS, insulin sensitivity; MCR, metabolic clearance rate; MO, Moderate intensity exercise at 35% VO2max; n.r., not reported; SCII variable subcutaneous insulin infusion; T1D, type 1 diabetes participants; T1Di, Type 1 diabetes

37

ACCEPTED MANUSCRIPT patients with intensive glycemic control; T1Dp, Type 1 diabetes patients with poor glycemic

AC

CE

PT

ED

MA NU

SC

RI P

T

control; w, week.

38

Insulin resistance in type 1 diabetes mellitus.

For long the presence of insulin resistance in type 1 diabetes has been questioned. Detailed metabolic analyses revealed 12%-61% and up to 20% lower w...
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