Insulin detemir for the treatment of obese patients with type 2 diabetes

Hollander, Priscilla

doi:10.2147/dmso.s26980

Cited by 15 publications

(8 citation statements)

References 56 publications

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“…Although a small HbA 1c reduction was seen in both groups, a small weight reduction was seen in the TI-Gen2 group, whereas a statistically significant weight gain occurred for the insulin aspart group. Although the mechanism is not known with certainty, reduced concern about hypoglycemia may lead to less "defensive" eating (15).…”

Section: Discussionmentioning

confidence: 99%

Inhaled Technosphere Insulin Compared With Injected Prandial Insulin in Type 1 Diabetes: A Randomized 24-Week Trial

et al. 2015

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OBJECTIVETo compare the efficacy and safety of Technosphere insulin (TI) and insulin aspart in patients with type 1 diabetes. RESEARCH DESIGN AND METHODSThis open-label noninferiority trial compared the change in HbA 1c from baseline to week 24 of prandial TI (n = 174) with that of subcutaneous aspart (n = 171), both with basal insulin, in patients with type 1 diabetes and HbA 1c 7.5-10.0% (56.8-86.0 mmol/mol). RESULTSMean change in HbA 1c in TI patients (-0.21% [-2.3 mmol/mol]) from baseline (7.94% [63.3 mmol/mol]) was noninferior to that in aspart patients (-0.40% [-4.4 mmol/mol]) from baseline (7.92% [63.1 mmol/mol]). The between-group difference was 0.19% (2.1 mmol/mol) (95% CI 0.02-0.36), satisfying the noninferiority margin of 0.4%. However, more aspart patients achieved HbA 1c <7.0% (53.0 mmol/mol) (30.7% vs. 18.3%). TI patients had a small weight loss (-0.4 kg) compared with a gain (+0.9 kg) for aspart patients (P = 0.0102). TI patients had a lower hypoglycemia event rate than aspart patients (9.8 vs. 14.0 events/patient-month, P < 0.0001). Cough (generally mild) was the most frequent adverse event (31.6% with TI, 2.3% with aspart), leading to discontinuation in 5.7% of patients. Treatment group difference for mean change from baseline in forced expiratory volume in 1 s was small (40 mL) and disappeared upon TI discontinuation. CONCLUSIONSIn patients with type 1 diabetes receiving basal insulin, HbA 1c reduction with TI was noninferior to that of aspart, with less hypoglycemia and less weight gain but increased incidence of cough.

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Section: Discussionmentioning

confidence: 99%

Inhaled Technosphere Insulin Compared With Injected Prandial Insulin in Type 1 Diabetes: A Randomized 24-Week Trial

et al. 2015

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“…In this study, (14), and preferential inhibition of hepatic glucose production vs. peripheral glucose uptake (19). Our investigation using the obese diabetic db/db mouse model demonstrated that d-INS but not h-INS increased circulating GLP-1 levels, which were associated with decreased weight gain, reduced food intake, and improved glucose homeostasis.…”

Section: Discussionmentioning

confidence: 67%

“…It is noted that d-INS can exert its actions in other tissues or organs to contribute to its weight-sparing effects. One such example is that d-INS increases adiponectin levels, which is associated with both weight loss and reduced food intake in diabetic rats (19). A recent study by Schinner and colleagues (37) has demonstrated that adipocyte-derived Wnt signaling molecules could enhance ␤-cell proliferation and secretion, suggesting that cross talk between Wnt and insulin signaling could occur at intraorgan levels to exert physiological or pathophysiological relevance.…”

Section: Discussionmentioning

confidence: 99%

Insulin detemir enhances proglucagon gene expression in the intestinal L cells via stimulating β-catenin and CREB activities

Liu

Chiang

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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Insulin therapy using insulin detemir (d-INS) has demonstrated weight-sparing effects compared with other insulin formulations. Mechanisms underlying these effects, however, remain largely unknown. Here we postulate that the intestinal tissues' selective preference allows d-INS to exert enhanced action on proglucagon (Gcg) expression and the production of glucagon-like peptide (GLP)-1, an incretin hormone possessing both glycemia-lowering and weight loss effects. To test this hypothesis, we used obese type 2 diabetic db/db mice and conducted a 14-day intervention with daily injection of a therapeutic dose of d- insulin; protein kinase B; glycogen synthase kinase-3; extracellular signal-regulated kinase; ␤-catenin; adenosine 3=,5=-cyclic monophosphate response element-binding protein; Wnt; proglucagon; gut; L cells INSULIN THERAPY IS A CRITICAL treatment for type 1 diabetes patients, and it is also becoming increasingly accepted for type 2 diabetes for the reduction of diabetic complications (48). Weight gain is a primary adverse effect in both type 1 and type 2 diabetic patients on insulin therapy (7, 50). However, patients using long-acting insulin analogs, particularly insulin detemir (d-INS), often show decreased weight gain (16,39).Insulin exerts a variety of biological effects through activation of its cell surface receptor (43). Activation of phosphatidylinositol 3-kinase (PI3-K) and protein kinase B (Akt) is a critical event that triggers diverse downstream signaling cascades and effector responses (23). In the periphery, activation of this pathway conveys insulin actions such as glucose transport, gene transcription, and protein synthesis (23, 53). In the brain, integral insulin signaling via the PI3-K/Akt pathway is related to nutrient homeostasis and appetite regulation (36).d-INS has a fatty acid chain addition at LysB29 that permits reversible albumin binding (15). Diabetic patients with d-INS therapy usually show both improved glycemic control and weight stability (16, 18) compared with other basal insulin therapies. The molecular mechanisms underlying the weightsparing benefit of d-INS remain largely unknown. It has been proposed that d-INS could cross the blood-brain barrier faster and in higher quantities than other types of insulin to induce stronger effect in the brain (17). As a result, reduced appetite may contribute to its weight-sparing benefit (4).We have demonstrated recently that insulin stimulates proglucagon (Gcg) expression in the intestinal endocrine L cells but not in the pancreatic ␣-cells (53). In colon cancer cells, insulin stimulates ␤-catenin (␤-cat) Ser 675 phosphorylation, which was associated with enhanced nuclear localization of ␤-cat and the binding of ␤-cat/TCF7L2 to Wnt target promoters (41). The bipartite transcription factor ␤-cat/TCF is the key downstream effector in the Wnt signaling pathway while the phosphorylation of ␤-cat at Ser 675 increases its nuclear translocation (44). Interestingly, insulin appears to use the same cisand trans-elements that are used by the ...

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“…This alteration promotes the binding of DET to blood albumin, which prolongs its life in the circulation and selectively enhances its uptake into hepatic and central nervous system (CNS) tissue (13,25,26). Clinical trials have demonstrated that DET has a significant weight-gain-sparing effect in diabetic patients, in contrast to other long-acting forms of insulin (14,15). However, the mechanism underlying this effect remains unknown.…”

mentioning

confidence: 99%

“…However, the mechanism underlying this effect remains unknown. Among the hypotheses proposed for the weight-sparing effect of DET is the possibility of enhanced CNS catabolic effects of this insulin analog (14,15,23).…”

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confidence: 99%

Central effects of insulin detemir on feeding, body weight, and metabolism in rats

Vasselli

Pi‐Sunyer

Wall

et al. 2017

American Journal of Physiology-Endocrinology and Metabolism

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Insulin detemir (DET) is a basal insulin analog that, in contrast to other long-acting forms of insulin, has significant weight-gain-sparing effects in diabetic patients. We hypothesized that this effect of DET may be due to its enhanced catabolic action in the central nervous system. We investigated the long-term effects of single third ventricular (3V) microinjections of equimolar doses of DET and regular insulin in normal male rats on feeding, body weight, energy expenditure (EE), and respiratory quotient (RQ). Also, in acute testing, we assessed the ability of lower doses of DET to alter feeding, EE, and RQ when microinjected directly into the paraventricular nucleus (PVN). The anabolic peptide ghrelin served as a positive control in acute testing. 3V administration of both DET (0.5-2.0 mU) and regular insulin (2.0-8.0 mU) significantly reduced feeding and body weight over 48 and 120 h, respectively, with DET yielding greater inhibitory effects. DET also stimulated greater elevations of EE and reductions of RQ over 72 and 48 h postinjection, respectively. In acute (4 h) testing, microinjections of DET (0.5 mU) into the PVN reduced feeding, increased EE, and reduced RQ, while ghrelin (100 pmol) had the opposite effects. When administered sequentially into the PVN, DET (0.25 and 0.5 mU) reversed ghrelin-induced feeding, EE, and RQ effects. These data support the notion that the weight-sparing effect of DET is at least in part based on its central catabolic action and that enhanced EE and reduced RQ may participate in this effect.

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Insulin detemir for the treatment of obese patients with type 2 diabetes

Cited by 15 publications

References 56 publications

Inhaled Technosphere Insulin Compared With Injected Prandial Insulin in Type 1 Diabetes: A Randomized 24-Week Trial

Inhaled Technosphere Insulin Compared With Injected Prandial Insulin in Type 1 Diabetes: A Randomized 24-Week Trial

Insulin detemir enhances proglucagon gene expression in the intestinal L cells via stimulating β-catenin and CREB activities

Central effects of insulin detemir on feeding, body weight, and metabolism in rats

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