Effects of insulin therapy on weight gain and fat distribution in the HF/HS-STZ rat model of type 2 diabetes

Skovsø, Søs; Damgaard, Jesper; Fels, Johannes; Olsen, Grith Skytte; Wolf, Xenia Asbæk; Rolin, Bidda; Holst, Jens J.

doi:10.1038/ijo.2015.92

Cited by 25 publications

(17 citation statements)

References 47 publications

(52 reference statements)

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“…Moreover, across multiple models, we found that obesity and lipid homeostasis are more sensitive to small changes in circulating insulin levels than glucose homeostasis. Collectively, these experiments also fit well with clinical and pre-clinical studies demonstrating that therapy with long-acting insulin analogues leads to weight gain, and with small trials showing weight loss with drugs that reduce insulin secretion (Alemzadeh et al 1998, Lustig et al 2005, ORIGIN Trial Investigators et al 2012, Skovso et al 2015. For example, a recent investigation reported that chronic insulin infusion via mini-osmotic pump leads to WAT expansion in mice (Rajan et al 2016).…”

Section: :3supporting

confidence: 56%

“…Subcutaneous and visceral depots of WAT have distinct characteristics, differing in cellular composition, innervation, metabolic characteristics and secretory profile; in general, visceral WAT is more implicated in perpetuating metabolic dysfunction, compared to subcutaneous WAT (Lee et al 2013, Lim et al 2015. Interestingly, insulin treatment may have selective trophic effects on subcutaneous WAT when compared with visceral WAT in a rat model of latestage type 2 diabetes (Skovso et al 2015). The mechanisms regulating the specific expansion of distinct WAT depots are not well understood, although physiological factors such as age and sex have an influence on adipose tissue distribution (Fuente-Martin et al 2013, Lee et al 2013, Jeffery et al 2016, Kwok et al 2016.…”

Section: Direct Mechanisms By Which Insulin May Influence Obesitymentioning

confidence: 99%

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A causal role for hyperinsulinemia in obesity

Templeman

Skovsø

Page

et al. 2017

Journal of Endocrinology

130

116

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Insulin modulates the biochemical pathways controlling lipid uptake, lipolysis and lipogenesis at multiple levels. Elevated insulin levels are associated with obesity, and conversely, dietary and pharmacological manipulations that reduce insulin have occasionally been reported to cause weight loss. However, the causal role of insulin hypersecretion in the development of mammalian obesity remained controversial in the absence of direct loss-of-function experiments. Here, we discuss theoretical considerations around the causal role of excess insulin for obesity, as well as recent studies employing mice that are genetically incapable of the rapid and sustained hyperinsulinemia that normally accompanies a high-fat diet. We also discuss new evidence demonstrating that modest reductions in circulating insulin prevent weight gain, with sustained effects that can persist after insulin levels normalize. Importantly, evidence from long-term studies reveals that a modest reduction in circulating insulin is not associated with impaired glucose homeostasis, meaning that body weight and lipid homeostasis are actually more sensitive to small changes in circulating insulin than glucose homeostasis in these models. Collectively, the evidence from new studies on genetic loss-of-function models forces a re-evaluation of current paradigms related to obesity, insulin resistance and diabetes. The potential for translation of these findings to humans is briefly discussed.

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Section: :3supporting

confidence: 56%

Section: Direct Mechanisms By Which Insulin May Influence Obesitymentioning

confidence: 99%

A causal role for hyperinsulinemia in obesity

Templeman

Skovsø

Page

et al. 2017

Journal of Endocrinology

130

116

View full text Add to dashboard Cite

show abstract

“…458 This indicates that additional factors to hyperglycemia and insulin resistance are necessary for muscle loss in T2D. In a rat model of T2D, insulin therapy was shown to improve lean mass 459 ; however, in humans with T2D, insulin therapy is considered to be ineffective for improving muscle mitochondrial function, 460 increasing protein synthesis, 461 reversing skeletal muscle proteolysis, 462 or improving muscle strength. 463 Furthermore, insulin therapy in patients with newly diagnosed T2D was not associated with skeletal muscle gain 455,464 contrary to patients with T1D.…”

Section: Diabetic Pharmacotherapy: Effects On Skeletal Musclementioning

confidence: 99%

Diabetes pharmacotherapy and effects on the musculoskeletal system

Kalaitzoglou

Fowlkes

Popescu

et al. 2018

Diabetes Metabolism Res

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Summary Persons with type 1 or type 2 diabetes have a significantly higher fracture risk than age‐matched persons without diabetes, attributed to disease‐specific deficits in the microarchitecture and material properties of bone tissue. Therefore, independent effects of diabetes drugs on skeletal integrity are vitally important. Studies of incretin‐based therapies have shown divergent effects of different agents on fracture risk, including detrimental, beneficial, and neutral effects. The sulfonylurea class of drugs, owing to its hypoglycemic potential, is thought to amplify the risk of fall‐related fractures, particularly in the elderly. Other agents such as the biguanides may, in fact, be osteo‐anabolic. In contrast, despite similarly expected anabolic properties of insulin, data suggests that insulin pharmacotherapy itself, particularly in type 2 diabetes, may be a risk factor for fracture, negatively associated with determinants of bone quality and bone strength. Finally, sodium‐dependent glucose co‐transporter 2 inhibitors have been associated with an increased risk of atypical fractures in select populations, and possibly with an increase in lower extremity amputation with specific SGLT2I drugs. The role of skeletal muscle, as a potential mediator and determinant of bone quality, is also a relevant area of exploration. Currently, data regarding the impact of glucose lowering medications on diabetes‐related muscle atrophy is more limited, although preclinical studies suggest that various hypoglycemic agents may have either aggravating (sulfonylureas, glinides) or repairing (thiazolidinediones, biguanides, incretins) effects on skeletal muscle atrophy, thereby influencing bone quality. Hence, the therapeutic efficacy of each hypoglycemic agent must also be evaluated in light of its impact, alone or in combination, on musculoskeletal health, when determining an individualized treatment approach. Moreover, the effect of newer medications (potentially seeking expanded clinical indication into the pediatric age range) on the growing skeleton is largely unknown. Herein, we review the available literature regarding effects of diabetes pharmacotherapy, by drug class and/or by clinical indication, on the musculoskeletal health of persons with diabetes.

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“…In this study, a T2-DM rat model was successfully established with high-fat diet and STZ injection (Skovsø et al, 2015;Chen et al, 2016). Thereafter, the mechanisms underlying the hepatoprotective effect of ginsenoside Rg1 in the T2-DM rat were investigated.…”

Section: Discussionmentioning

confidence: 99%

Effects of ginsenoside Rg1 on glucose metabolism and liver injury in streptozotocin-induced type 2 diabetic rats

Tian¹,

Chen²,

Zhang³

et al. 2017

Genet. Mol. Res.

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Type 2 diabetes mellitus (T2-DM) is a chronic metabolic disorder characterized by high blood glucose levels. T2-DM patients suffer from many complications, such as diabetic fatty liver and diabetic nephropathy. The liver, the pivotal organ involved in both glucose and lipid metabolism, is primarily damaged in T2-DM patients, especially in those with high levels of blood lipid. In this study, the hepatoprotective activity of ginsenoside Rg1 was investigated in a T2-DM rat model. The results revealed a potent hepatoprotective effect of ginsenoside Rg1. This effect was primarily mediated by the antiapoptotic effect, inhibition of JNK activity, and suppression of inflammation after ginsenoside Rg1 treatment. Ginsenoside Rg1 also lowered the blood glucose level and insulin resistance index in T2-DM rats. Moreover, the blood lipid profile (total cholesterol, triglycerides, and low-density lipoprotein cholesterol levels) and liver function (aspartate transaminase and alanine transaminase levels) improved after ginsenoside Rg1 treatment. The aforementioned hepatoprotective effects of ginsenoside Rg1 in the T2-DM rat model suggests its clinical potential as an adjuvant drug for T2-DM therapy, especially for T2-DM patients with fatty liver disease.

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Effects of insulin therapy on weight gain and fat distribution in the HF/HS-STZ rat model of type 2 diabetes

Cited by 25 publications

References 47 publications

A causal role for hyperinsulinemia in obesity

A causal role for hyperinsulinemia in obesity

Diabetes pharmacotherapy and effects on the musculoskeletal system

Effects of ginsenoside Rg1 on glucose metabolism and liver injury in streptozotocin-induced type 2 diabetic rats

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