Sustained Diabetes Remission Research Articles

Aetiology of Type 2 diabetes in people with a 'normal' body mass index: testing the personal fat threshold hypothesis.

Weight loss in overweight or obese individuals with Type 2 diabetes (T2D) can normalize hepatic fat metabolism, decrease fatty acid oversupply to β cells and restore normoglycaemia. One in six people has BMI <27 kg/m2 at diagnosis, and their T2D is assumed to have different aetiology. The Personal Fat Threshold hypothesis postulated differing individual thresholds for lipid overspill and adverse effects on β-cell function. To test this hypothesis, people with Type 2 diabetes and body mass index <27kg/m2 (n = 20) underwent repeated 5% weight loss cycles. Metabolic assessments were carried out at stable weight after each cycle and after 12 months. To determine how closely metabolic features returned to normal, 20 matched normoglycemic controls were studied once. Between baseline and 12 months: BMI fell (mean ± SD), 24.8 ± 0.4 to 22.5 ± 0.4 kg/m2 (P<0.0001) (controls: 21.5 ± 0.5); total body fat, 32.1 ± 1.5 to 27.6 ± 1.8% (P<0.0001) (24.6 ± 1.5). Liver fat content and fat export fell to normal as did fasting plasma insulin. Post-meal insulin secretion increased but remained subnormal. Sustained diabetes remission (HbA1c < 48 mmol/mol off all glucose-lowering agents) was achieved by 70% (14/20) by initial weight loss of 6.5 (5.5-10.2)%. Correction of concealed excess intra-hepatic fat reduced hepatic fat export, with recovery of β-cell function, glycaemic improvement in all and return to a non-diabetic metabolic state in the majority of this group with BMI <27 kg/m2 as previously demonstrated for overweight or obese groups. The data confirm the Personal Fat Threshold hypothesis: aetiology of Type 2 diabetes does not depend on BMI. This pathophysiological insight has major implications for management.

Sustained inhibition of NPY/AgRP neuronal activity by FGF1.

In rodent models of type 2 diabetes (T2D), central administration of FGF1 normalizes elevated blood glucose levels in a manner that is sustained for weeks or months. Increased activity of NPY/AgRP neurons in the hypothalamic arcuate nucleus (ARC) is implicated in the pathogenesis of hyperglycemia in these animals, and the ARC is a key brain area for the antidiabetic action of FGF1. We therefore sought to determine whether FGF1 inhibits NPY/AgRP neurons and, if so, whether this inhibitory effect is sufficiently durable to offer a feasible explanation for sustained diabetes remission induced by central administration of FGF1. Here, we show that FGF1 inhibited ARC NPY/AgRP neuron activity, both after intracerebroventricular injection in vivo and when applied ex vivo in a slice preparation; we also showed that the underlying mechanism involved increased input from presynaptic GABAergic neurons. Following central administration, the inhibitory effect of FGF1 on NPY/AgRP neurons was also highly durable, lasting for at least 2 weeks. To our knowledge, no precedent for such a prolonged inhibitory effect exists. Future studies are warranted to determine whether NPY/AgRP neuron inhibition contributes to the sustained antidiabetic action elicited by intracerebroventricular FGF1 injection in rodent models of T2D.

Metabolites and diabetes remission after weight loss

There is marked heterogeneity in the response to weight loss interventions with regards to weight loss amount and metabolic improvement. We sought to identify biomarkers predictive of type 2 diabetes remission and amount of weight loss in individuals with severe obesity enrolled in the Longitudinal Assessment of Bariatric Surgery (LABS) and the Look AHEAD (Action for Health in Diabetes) studies. Targeted mass spectrometry-based profiling of 135 metabolites was performed in pre-intervention blood samples using a nested design for diabetes remission over five years (n = 93 LABS, n = 80 Look AHEAD; n = 87 remitters), and for extremes of weight loss at five years (n = 151 LABS; n = 75 with high weight loss). Principal components analysis (PCA) was used for dimensionality reduction, with PCA-derived metabolite factors tested for association with both diabetes remission and weight loss. Metabolic markers were tested for incremental improvement to clinical models, including the DiaRem score. Two metabolite factors were associated with diabetes remission: one primarily composed of branched chain amino acids (BCAA) and tyrosine (odds ratio (95% confidence interval) [OR (95% CI)] = 1.4 [1.0–1.9], p = 0.045), and one with betaine and choline (OR [95% CI] = 0.7 [0.5–0.9], p = 0.02).These results were not significant after adjustment for multiple tests. Inclusion of these two factors in clinical models yielded modest improvements in model fit and performance: in a constructed clinical model, the C-statistic improved from 0.87 to 0.90 (p = 0.02), while the net reclassification index showed improvement in prediction compared to the DiaRem score (NRI = 0.26, p = 0.0013). No metabolite factors associated with weight loss at five years. Baseline levels of metabolites in the BCAA and trimethylamine-N-oxide (TMAO)-microbiome-related pathways are independently and incrementally associated with sustained diabetes remission after weight loss interventions in individuals with severe obesity. These metabolites could serve as clinically useful biomarkers to identify individuals who will benefit the most from weight loss interventions.

Erratum. The Hypothalamic Arcuate Nucleus-Median Eminence Is a Target for Sustained Diabetes Remission Induced by Fibroblast Growth Factor 1. Diabetes 2019;68:1054-1061.

Erratum. The Hypothalamic Arcuate Nucleus-Median Eminence Is a Target for Sustained Diabetes Remission Induced by Fibroblast Growth Factor 1. Diabetes 2019;68:1054-1061.

Hypothalamic perineuronal net assembly is required for sustained diabetes remission induced by fibroblast growth factor 1 in rats.

We recently showed that perineuronal nets (PNNs) enmesh glucoregulatory neurons in the arcuate nucleus (Arc) of the mediobasal hypothalamus (MBH)1, but whether these PNNs play a role in either the pathogenesis of type 2 diabetes (T2D) or its treatment remains unclear. Here we show that PNN abundance within the Arc is markedly reduced in the Zucker diabetic fatty (ZDF) rat model of T2D, compared with normoglycaemic rats, correlating with altered PNN-associated sulfation patterns of chondroitin sulfate glycosaminoglycans in the MBH. Each of these PNN-associated changes is reversed following a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1) at a dose that induces sustained diabetes remission in male ZDF rats. Combined with previous work localizing this FGF1 effect to the Arc area2-4, our finding that enzymatic digestion of Arc PNNs markedly shortens the duration of diabetes remission following icv FGF1 injection in these animals identifies these extracellular matrix structures as previously unrecognized participants in the mechanism underlying diabetes remission induced by the central action of FGF1.

Transcriptomic analysis links diverse hypothalamic cell types to fibroblast growth factor 1-induced sustained diabetes remission

In rodent models of type 2 diabetes (T2D), sustained remission of hyperglycemia can be induced by a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1), and the mediobasal hypothalamus (MBH) was recently implicated as the brain area responsible for this effect. To better understand the cellular response to FGF1 in the MBH, we sequenced >79,000 single-cell transcriptomes from the hypothalamus of diabetic Lepob/ob mice obtained on Days 1 and 5 after icv injection of either FGF1 or vehicle. A wide range of transcriptional responses to FGF1 was observed across diverse hypothalamic cell types, with glial cell types responding much more robustly than neurons at both time points. Tanycytes and ependymal cells were the most FGF1-responsive cell type at Day 1, but astrocytes and oligodendrocyte lineage cells subsequently became more responsive. Based on histochemical and ultrastructural evidence of enhanced cell-cell interactions between astrocytes and Agrp neurons (key components of the melanocortin system), we performed a series of studies showing that intact melanocortin signaling is required for the sustained antidiabetic action of FGF1. These data collectively suggest that hypothalamic glial cells are leading targets for the effects of FGF1 and that sustained diabetes remission is dependent on intact melanocortin signaling.

Ten-year remission rates in insulin-treated type 2 diabetes after biliopancreatic diversion with duodenal switch.

Biliopancreatic diversion with duodenal switch (BPD-DS) confers the highest rate of type 2 diabetes (T2D) remission compared with other bariatric procedures. Previous studies suggest that type of antidiabetic therapy used before surgery and duration of disease influence postsurgical glycemic outcomes. Short-term, progressive improvement in insulin sensitivity and beta-cell function after metabolic surgery in patients with noninsulin-treated T2D has been demonstrated. Whether patients with more advanced disease can achieve sustained remission remains unclear. The aim of this study was to assess long-term glycemic outcomes in insulin-treated patients with T2D after BPD-DS and identify predictors of sustained diabetes remission or relapse. University-affiliated tertiary care center. Data from 141 patients with insulin-treated T2D who underwent BPD-DS between 1994 and 2006 with 10 years of follow-up data were collected from a prospective electronic database. Follow-up was available in 132 patients (91%). At 10 years after metabolic surgery, 90 patients (68.1%) had a complete remission of diabetes, 3 (2.3%) had a partial remission, 21 (15.9%) had an improvement, and 3 (2.3%) were unchanged in their diabetes status. Fourteen patients died during the 10-year follow-up period. Relapse after an initial period of remission occurred in 15 (11.4%) patients. Insulin discontinuation was achieved in 97%. Duration of diabetes was an independent predictor of nonremission at 10 years. The BPD-DS maintains remission at 10 years postoperatively in patients with more advanced diabetes. Long-term benefits of the BPD-DS on weight loss and glycemic control should be considered when offering metabolic surgery to patients with insulin-treated T2D.

214-OR: Role of Hypothalamic MAPK/ERK Signaling in Diabetes Remission Induced by the Central Action of Fibroblast Growth Factor 1 (FGF1)

The hypothalamic arcuate nucleus-median eminence (ARC-ME) is a target for sustained diabetes remission induced by fibroblast growth factor 1 (FGF1). To identify intracellular signaling cascades underlying this effect, we considered evidence that sustained signal transduction responses engaged by FGF1 are integrin-dependent. To determine if the sustained antidiabetic response of diabetic ob/ob mice to intracerebroventricular (icv) injection of FGF1 is also integrin-dependent, we investigated the response to a mutant FGF1 that is unable to activate integrin receptors (R50E FGF1). We found that although icv injection of R50E FGF1 mimics the transient anorexia, weight loss and blood glucose lowering responses induced by native FGF1 (P&amp;lt;0.001 vs. Veh for each), it fails to elicit sustained diabetes remission. Similarly, MAPK/ERK signaling is induced in the ARC-ME (primarily in tanycytes) for up to 24 h following a single icv FGF1 injection in both wild type and ob/ob mice, but the duration of this response is reduced by∼70% following icv R50E FGF1 injection (P&amp;lt;0.0001 vs. icv FGF1). We therefore hypothesized that owing to its integrin-dependent nature, FGF1-induced remission of diabetic hyperglycemia requires sustained activation of the MAPK/ERK signaling pathway in the ARC-ME. To test this hypothesis, 4 groups of diabetic ob/ob mice were studied. Each group received a single icv injection of either saline vehicle or recombinant FGF1 (3 µg), followed immediately by continuous icv infusion of either the MAPK inhibitor U0126 or its vehicle (DMSO) for 24 h. We report that the duration of the antidiabetic effect induced by icv FGF1 injection is attenuated by pharmacologic blockade of MAPK/ERK signaling. We conclude that the sustained remission of diabetic hyperglycemia induced by the central action of FGF1 depends upon its ability to activate hypothalamic MAPK/ERK signaling in a sustained manner. Disclosure J.M. Brown: None. B.N. Phan: None. H. Wasanwala: None. M.E. Matsen: None. A. Secher: Employee; Spouse/Partner; Gubra. Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. G.J. Morton: Research Support; Self; Novo Nordisk A/S. M.W. Schwartz: Research Support; Self; Novo Nordisk A/S. J. Scarlett: None. Funding National Institutes of Health (K08DK114474, DK101997, DK083042, DK035816, P30DK017047, HL007312); University of Washington

1771-P: Hypothalamic Perineuronal Net Assembly Is Required for Sustained Diabetes Remission Induced by FGF1

Defective glucoregulatory neurocircuit activity within the hypothalamic arcuate nucleus (ARC) is implicated in the pathogenesis of type 2 diabetes (T2D). In the ARC of T2D-Zucker Diabetic Fatty (ZDF) rats, we have identified significant changes in the composition and abundance of extracellular perineuronal nets (PNNs) that enmesh glucoregulatory neurocircuits. Imaging of ARC PNNs, which are comprised of the chondroitin sulfate (CS) proteoglycan aggrecan and attached CS glycosaminoglycans (GAGs), show that T2D-ZDF rats exhibit a 66.4% and 77.3% decrease in aggrecan in the medial and lateral ARC areas, respectively, compared to normoglycemic controls. Distinctive sulfation of the attached CS-GAG isomers (0S-, 4S-, 6S-, 4S6S-, 2S6S-CS) differentially influence the function of PNNs. Using LC-MS/MS, we provide the first description of hypothalamic CS-GAG sulfation patterns and show that in T2D-ZDF rats, levels of the ∆4S- isomer is increased, whereas ∆6S- and ∆2S6S-CS isomers are decreased, differences predicted to disrupt protein-GAG interactions involved in neurite outgrowth and favor tissue stiffening. To determine if ARC PNNs are targets for the antidiabetic effect of fibroblast growth factor 1 (FGF1), we performed intracerebroventricular (icv) injection of FGF1 in ZDF rats and report that both the hypothalamic CS-GAG sulfation patterns and content of ARC PNNs are normalized 24 d after treatment. Western blot analysis shows that the latter effect entails a 1.7-fold increase in aggrecan protein abundance. To assess the functional significance of ARC PNN restoration by FGF1, ZDF rats received an icv FGF1 injection followed by bilateral microinjection of either ChABC, a PNN digesting enzyme, or its vehicle control into the ARC. Our finding that the duration of sustained FGF1-induced blood glucose lowering was shortened following ARC PNN digestion (p&amp;lt;0.05) identifies PNNs as novel participants in the central control of glucose homeostasis and diabetes remission by FGF1. Disclosure K.M. Alonge: Research Support; Self; Novo Nordisk Inc. Z. Mirzadeh: None. J. Scarlett: None. A. Logsdon: None. J.M. Brown: None. E. Cabrales: None. C.K. Chan: None. K. Kaiyala: None. M.A. Bentsen: None. W.A. Banks: None. M. Guttman: None. T.N. Wight: None. G.J. Morton: Research Support; Self; Novo Nordisk A/S. M.W. Schwartz: Research Support; Self; Novo Nordisk A/S. Funding National Institutes of Health (P30DK017047, F32DK122662, R01DK101997, R01DK089056, R01DK083042, K08DK114474, R01GM127579, K12NS080223, P30DK035816); Barrow Neurological Foundation (1800253005); University of Washington; Novo Nordisk (CMS431104); Novo Nordisk Foundation (NNF170C0024328, NNF10CC1016515)

Remission of Type 2 Diabetes Following a Short-term Intervention With Insulin Glargine, Metformin, and Dapagliflozin.

To examine diabetes remission following a short-term intensive metabolic intervention combining lifestyle and glucose-lowering approaches. We conducted an open-label, randomized controlled trial in 154 patients with type 2 diabetes up to 8 years in duration on 0 to 2 glucose-lowering medications. Participants were randomized to (a) a 12-week intensive intervention comprising lifestyle approaches and treatment with insulin glargine, metformin, and dapagliflozin or (b) standard diabetes care. At 12 weeks, diabetes medications were discontinued in participants with hemoglobin A1c (HbA1C) < 7.3% (56 mmol/mol). Participants were then followed for diabetes relapse until 64 weeks. The primary outcome was complete or partial diabetes remission (HbA1C < 6.5% [48 mmol/mol] off chronic diabetes drugs) at 24 weeks. Main secondary outcomes were complete or partial diabetes remission at 36, 48, and 64 weeks. The primary outcome was achieved in 19 (24.7%) intervention group participants and 13 (16.9%) control group participants at 24 weeks (relative risk [RR] 1.5; 95% confidence interval [CI], 0.8-2.7). The relative risks of remission at 36, 48, and 64 weeks were 2.4 (95% CI, 1.2-5.0), 2.1 (95% CI, 1.0-4.4), and 1.8 (95% CI, 0.7-4.7), respectively. In an exploratory analysis, the intervention reduced the hazard of diabetes relapse with overt hyperglycemia by 43% (hazard ratio 0.57; 95% CI, 0.39-0.81). Our primary outcome of diabetes remission at 24 weeks was not statistically significantly different. However, our overall results suggest that some patients with early type 2 diabetes are able to achieve sustained diabetes remission following a short-term intensive intervention. Further studies are needed to optimize the combined therapeutic approach used.

Adjunctive liraglutide treatment in patients with persistent or recurrent type 2 diabetes after metabolic surgery (GRAVITAS): a randomised, double-blind, placebo-controlled trial

Many patients with type 2 diabetes do not achieve sustained diabetes remission after metabolic (bariatric) surgery for the treatment of obesity. Liraglutide, a glucagon-like peptide-1 analogue, improves glycaemic control and reduces bodyweight in patients with type 2 diabetes. Our aim was to assess the safety and efficacy of liraglutide 1·8 mg in patients with persistent or recurrent type 2 diabetes after metabolic surgery. In the GRAVITAS randomised double-blind, placebo-controlled trial, we enrolled adults who had undergone Roux-en-Y gastric bypass or vertical sleeve gastrectomy and had persistent or recurrent type 2 diabetes with HbA1c levels higher than 48 mmol/mol (6·5%) at least 1 year after surgery from five hospitals in London, UK. Participants were randomly assigned (2:1) via a computer-generated sequence to either subcutaneous liraglutide 1·8 mg once daily or placebo, both given together with a reduced-calorie diet, aiming for a 500 kcal per day deficit from baseline energy intake, and increased physical activity. The primary outcome was the change in HbA1c from baseline to the end of the study period at 26 weeks, assessed in patients who completed the trial. Safety was assessed in the safety analysis population, consisting of all participants who received either liraglutide or placebo. This trial is registered with EudraCT, number 2014-003923-23, and the ISRCTN registry, number ISRCTN13643081. Between Jan 29, 2016, and May 2, 2018, we assigned 80 patients to receive either liraglutide (n=53) or placebo (n=27). 71 (89%) participants completed the study and were included in the principal complete-cases analysis. In a multivariable linear regression analysis, with baseline HbA1c levels and surgery type as covariates, liraglutide treatment was associated with a difference of -13·3 mmol/mol (-1·22%, 95% CI -19·7 to -7·0; p=0·0001) in HbA1c change from baseline to 26 weeks, compared with placebo. Type of surgery had no significant effect on the outcome. 24 (45%) of 53 patients assigned to liraglutide and 11 (41%) of 27 assigned to placebo reported adverse effects: these were mainly gastrointestinal and in line with previous experience with liraglutide. There was one death during the study in a patient assigned to the placebo group, which was considered unrelated to study treatment. These findings support the use of adjunctive liraglutide treatment in patients with persistent or recurrent type 2 diabetes after metabolic surgery. JP Moulton Foundation.

1823-P: Evidence that Arcuate Nucleus Neurocircuit Remodeling Ameliorates Hyperglycemia in Type 2 Diabetes

Abnormal development of neurocircuits in the hypothalamic arcuate nucleus (ARC) is a common feature of genetic and acquired (e.g., postnatal overnutrition) models of obesity and type 2 diabetes (T2D). In leptin-deficient ob/ob mice, developmental defects occur both in efferent projections from the ARC to downstream circuits and in afferent GABAergic input onto ARC neurons. A developmental critical period (CP) has been proposed based on the temporally-restricted requirement for leptin, during the first month of life, to enable normal projections of ARC Agrp neurons in ob/ob mice. We recently described the formation of perineuronal nets (PNNs) around ARC Agrp neurons during the latter half of this CP, shortly following the peak of the postnatal leptin surge. PNNs, which are extracellular matrix specializations that restrict CP plasticity in neurons they enmesh, were overabundant in the ARC of adult ob/ob mice, suggesting that ARC neurocircuit dysfunction contributes to their metabolic phenotype. To remodel ARC neurocircuits containing PNN-enmeshed cells, we engrafted a special population of GABAergic inhibitory interneurons derived from the embryonic brain medial ganglionic eminence (MGE). Here we show that MGE interneurons derived from E13.5 GAD67-GFP embyros and transplanted bilaterally into the ob/ob ARC survive, integrate into local circuits, and form GABAergic synapses. Preliminary metabolic phenotyping shows that compared to vehicle injection, transplanted MGE cells (∼5000 MGE cells/ARC) induce a sustained reduction of hyperglycemia lasting for at least one month (1-month average BG: veh 301±12 vs. MGE 189±12 mg/dl, n=4/group, p=0.022) without significant effects on food intake or body weight. These findings suggest that sustained diabetes remission can be achieved by remodeling ARC neurocircuits through MGE cell transplantation. Disclosure Z. Mirzadeh: Consultant; Self; Novo Nordisk A/S. E. Cabrales: None. M.W. Schwartz: Consultant; Self; Novo Nordisk A/S. Research Support; Self; Novo Nordisk A/S. Funding National Institute of Neurological Disorders and Stroke

The Hypothalamic Arcuate Nucleus-Median Eminence Is a Target for Sustained Diabetes Remission Induced by Fibroblast Growth Factor 1.

In rodent models of type 2 diabetes (T2D), sustained remission of diabetic hyperglycemia can be induced by a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1). To identify the brain areas responsible for this effect, we first used immunohistochemistry to map the hypothalamic distribution of phosphorylated extracellular signal-related kinase 1/2 (pERK1/2), a marker of mitogen-activated protein kinase-ERK signal transduction downstream of FGF receptor activation. Twenty minutes after icv FGF1 injection in adult male Wistar rats, pERK1/2 staining was detected primarily in two hypothalamic areas: the arcuate nucleus-median eminence (ARC-ME) and the paraventricular nucleus (PVN). To determine whether an action of FGF1 localized to either the ARC-ME or the PVN is capable of mimicking the sustained antidiabetic effect elicited by icv FGF1, we microinjected either saline vehicle or a low dose of FGF1 (0.3 µg/side) bilaterally into either the ARC-ME area or PVN of Zucker Diabetic Fatty rats, a model of T2D, and monitored daily food intake, body weight, and blood glucose levels over a 3-week period. Whereas bilateral intra-arcuate microinjection of saline vehicle was without effect, remission of hyperglycemia lasting >3 weeks was observed following bilateral microinjection of FGF1 into the ARC-ME. This antidiabetic effect cannot be attributed to leakage of FGF1 into cerebrospinal fluid and subsequent action on other brain areas, since icv injection of the same total dose was without effect. Combined with our finding that bilateral microinjection of the same dose of FGF1 into the PVN was without effect on glycemia or other parameters, we conclude that the ARC-ME area (but not the PVN) is a target for sustained remission of diabetic hyperglycemia induced by FGF1.

An Action in the Hypothalamic Arcuate Nucleus Is Sufficient to Explain the Sustained Remission of Diabetes Induced by Central Administration of Fibroblast Growth Factor-1 (FGF-1)

Our recent finding that a single intracerebroventricular (icv) injection of FGF-1 elicits sustained diabetes remission in rodent models of type 2 diabetes supports a growing consensus that the brain is a key target for diabetes drug development. The current work was undertaken to pinpoint the brain area responsible for this action of FGF-1. To this end, we considered the following preliminary findings: 1) both FGF Receptor 1 and integrin receptor αvβ3 (known to be involved in sustained FGF-1 signaling) are concentrated in the hypothalamic arcuate nucleus (ARC), 2) neuronal activation and sustained induction of the MAP Kinase / ERK pathway occurs in this brain area following icv FGF-1 injection, and 3) labeled FGF-1 is concentrated in this area following icv injection. We therefore hypothesized that in rodent models of T2D, an action in the ARC (a brain area known to participate in glucose homeostasis) mediates the sustained diabetes remission elicited by icv FGF-1 injection. To test this hypothesis, we investigated whether a single microinjection of a low dose of FGF-1 into the ARC (0.3 µg bilaterally, for a total of 0.6 µg) can mimic the response elicited by icv injection of a higher dose (3.0 µg). We report that in Zucker Diabetic Fatty rats, a single microinjection of FGF-1 bilaterally into the ARC (via an indwelling dual guide cannula) induced remission of hyperglycemia lasting &amp;gt;3 week, whereas intra-arcuate microinjection of saline vehicle was without effect (P&amp;lt;0.vs. Veh). Since icv injection of the same FGF-1 dose (0.6 µg) had no significant effect on glycemia, sustained diabetes remission induced by intra-ARC microinjection of FGF-1 cannot be explained by leakage into ventricular cerebrospinal fluid. We conclude that an action in the ARC is sufficient to explain the effect of FGF-1 to induce sustained diabetes remission. Disclosure J.M. Brown: None. J. Scarlett: None. M.E. Matsen: None. A. Secher: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. Employee; Spouse/Partner; Gubra. R. Jorgensen: Employee; Self; Novo Nordisk Inc.. G.J. Morton: None. M.W. Schwartz: Consultant; Self; Novo Nordisk A/S. Research Support; Self; Novo Nordisk A/S.

Sustained Diabetes Remission Induced by the Central Action of Fibroblast Growth Factor-1 (FGF-1) Requires Activation of Integrin Receptor aνß3

The brain is implicated in the antidiabetic effects of members of the fibroblast growth factor (FGF) peptide family. Previously, we reported that a single intracerebroventricular (icv) injection of FGF-1 induces remission of hyperglycemia that is sustained for weeks in rodent models of type 2 diabetes (T2D). The integrin receptor ανβ3 plays a key role in FGF-1 signaling, and crosstalk between ανβ3 and the FGF-1-FGF receptor (FGF-R) complex is necessary for increased DNA synthesis and proliferation in cultured cells. These cellular responses downstream of FGF-1-FGFR-ανβ3 result from sustained (e.g., lasting for 5 hours) activation of the extracellular signal-regulated kinase (ERK) signal transduction pathway. In cultured fibroblasts, prolonged ERK activation induced by FGF-1 is not replicated with a mutant FGF-1 peptide (R50E) that activates FGFR normally, but does not activate ανβ3 signaling. Similarly, we report that whereas icv FGF-1 (3 µg) induces phosphorylation of ERK1/2 at both early (20 minute) and late (5 hr) time points in hypothalamic punches obtained from wild type mice, icv injection of the same dose of R50E elicited this effect only at the early time point. Thus, R50E fails to activate hypothalamic FGF-1-FGFR-ανβ3 signaling in vivo. To investigate whether activation of ανβ3 is required for the prolonged antidiabetic effect of icv FGF-1, diabetic ob/ob mice received a single injection of either vehicle (Veh), recombinant FGF-1 (3 µg), or R50E (3 µg). Whereas R50E mimicked the effect of native FGF-1 to reduce food intake, body weight and blood glucose for the first week after icv injection (P&amp;lt;0.001 vs. Veh), the mutant peptide failed to elicit the sustained diabetes remission observed in animals receiving icv FGF-1. We conclude that signaling by the full FGF-1-FGFR-ανβ3 complex is necessary for the effect of FGF-1 signaling in the brain to elicit sustained remission of diabetic hyperglycemia in rodent models of T2D. Disclosure J. Scarlett: None. J.M. Brown: None. B.N. Phan: None. E.L. Khav: None. M.E. Matsen: None. N.K. Acharya: None. H.T. Nguyen: None. A. Secher: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. Employee; Spouse/Partner; Gubra. R. Jorgensen: Employee; Self; Novo Nordisk Inc.. G.J. Morton: None. M.W. Schwartz: Consultant; Self; Novo Nordisk A/S. Research Support; Self; Novo Nordisk A/S.

Central injection of fibroblast growth factor 1 induces sustained remission of diabetic hyperglycemia in rodents.

Type 2 diabetes (T2D) is among the most common and costly disorders worldwide1. The goal of current medical management of T2D is to transiently ameliorate hyperglycemia through daily dosing of one or more anti-diabetic drugs. Hypoglycemia and weight are common side effects of therapy, and sustained disease remission is not obtainable with non-surgical approaches. Based on the potent glucose-lowering response elicited by activation of brain fibroblast growth factor (FGF) receptors2–4, we explored the anti-diabetic efficacy of centrally administered FGF1, which, unlike other FGF peptides, activates all FGF receptor subtypes5. We report that a single intracerebroventricular (i.c.v.) injection of FGF1 at a dose one-tenth of that needed for systemic anti-diabetic efficacy induces sustained diabetes remission in both mouse and rat models of T2D. This anti-diabetic effect is not secondary to weight loss, does not increase the risk of hypoglycemia, and involves a novel and incompletely understood mechanism for increasing glucose clearance from the bloodstream. We conclude that the brain has the inherent potential to induce diabetes remission and that brain FGF receptors are potential pharmacological targets for achieving this goal.

Drug treatments to restore vascular function and diabesity

Over the last decades, an escalating rate of type 2 diabetes has paralleled an epidemic rise in the prevalence of obesity. Both diabetes and obesity confer an increased risk of cardiovascular comorbidities, including hypertension, coronary artery disease and stroke. Vascular dysfunction, represented by impaired endothelial release of vasodilator substances or defective smooth muscle vasodilator reactivity, is the early stage of the process leading to atherosclerosis and a common finding in patients with diabesity. It is understandable, therefore, that effective treatments for diabesity should restore vascular function to prevent the development of cardiovascular disease. Recent evidence from clinical studies supports the efficacy of incretin-based antidiabetic therapies for vascular protection. Thus, glucose control with either DDP-4 inhibitor or GLP-1 receptor therapies seems associated with favorable effects on vascular function in diabetes and the metabolic syndrome. Another mechanism to counter excess plasma glucose and reduce body weight in these patients may rely on drug therapies targeting gut hormones, as suggested by the efficacy of bariatric surgery to produce both sustained weight loss and high diabetes remission rates. Also, as knowledge of the multifaceted vascular actions of adipokines and their dysregulation in patients with diabesity increases, these substances become attractive targets for treatments aimed at cardiovascular prevention. The increasing coexistence of diabetes and obesity presents complex treatment challenges owing to the elevated risk of developing cardiovascular complications. Hence, therapeutic strategies integrating glycemic control, weight loss and vascular protection are of the greatest importance to successfully counteract the health and economic burden posed by diabesity.