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Glucagon Levels During Short-Term SGLT2 Inhibition Are Largely Regulated by Glucose Changes in Patients With Type 2 Diabetes.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.ORCID iD: 0000-0001-5498-3899
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
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2019 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 104, no 1, p. 193-201Article in journal (Refereed) Published
Abstract [en]

Context: The mechanism mediating sodium glucose cotransporter-2 (SGLT2) inhibitor-associated increase in glucagon levels is unknown.

Objective: To assess short-term effects on glucagon, other hormones, and energy substrates after SGLT2 inhibition and whether such effects are secondary to glucose lowering. The impact of adding a dipeptidyl peptidase-4 inhibitor was addressed.

Design, Setting, and Patients: A phase 4, single-center, randomized, three-treatment crossover, open-label study including 15 patients with type 2 diabetes treated with metformin.

Interventions: Patients received a single-dose of dapagliflozin 10 mg accompanied by the following in randomized order: isoglycemic clamp (experiment DG); saline infusion (experiment D); or saxagliptin 5 mg plus saline infusion (experiment DS). Directly after 5-hour infusions, a 2-hour oral glucose tolerance test (OGTT) was performed.

Results: Glucose and insulin levels were stable in experiment DG and decreased in experiment D [P for difference (Pdiff) < 0.001]. Glucagon-to-insulin ratio (Pdiff < 0.001), and levels of glucagon (Pdiff < 0.01), nonesterified fatty acids (Pdiff < 0.01), glycerol (Pdiff < 0.01), and β-OH-butyrate (Pdiff < 0.05) were lower in DG vs D. In multivariate analysis, change in glucose level was the main predictor of change in glucagon level. In DS, glucagon and active GLP-1 levels were higher than in D, but glucose and insulin levels did not differ. During OGTT, glucose levels rose less and glucagon levels fell more in DS vs D.

Conclusion: The degree of glucose lowering markedly contributed to regulation of glucagon and insulin secretion and to lipid mobilization during short-term SGLT2 inhibition.

Place, publisher, year, edition, pages
2019. Vol. 104, no 1, p. 193-201
National Category
Endocrinology and Diabetes
Identifiers
URN: urn:nbn:se:uu:diva-373521DOI: 10.1210/jc.2018-00969ISI: 000461917800025PubMedID: 30137410OAI: oai:DiVA.org:uu-373521DiVA, id: diva2:1278913
Available from: 2019-01-15 Created: 2019-01-15 Last updated: 2019-04-10Bibliographically approved
In thesis
1. Metabolic and endocrine effects of SGLT2 inhibition
Open this publication in new window or tab >>Metabolic and endocrine effects of SGLT2 inhibition
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Obesity and type 2 diabetes (T2D) are two growing global health problems with similar comorbidity profiles. SGLT2 inhibitors (SGLT2i) improve blood glucose control and can relieve both T2D and obesity, as well as their associated health problems such as hypertension, kidney failure, and cardiovascular disease.

In paper I, 50 obese patients without diabetes were treated for 24 weeks with SGLT2i dapagliflozin + GLP-1 receptor agonist (GLP-1RA) exenatide or placebo. They were examined regarding body weight loss and body composition. The placebo-adjusted weight loss was 4.13 kg, mostly attributable to adipose tissue loss.

In paper II, 43 completers of the study in paper I entered a 28-week extension phase in which all participants received active treatment. We found major reductions in body weight, adipose tissue volume, blood pressure and prediabetes that were sustained at 52 weeks. 

In paper III, 84 patients with T2D and non-alcoholic fatty liver disease underwent a 12-week treatment with dapagliflozin, omega-3 (n-3) carboxylic acids (OM-3CA), the combination of both or placebo to assess effects on liver fat content. MRI showed significant reductions of liver fat versus baseline and, for the combination, versus placebo.

In paper IV: 15 metformin-treated patients with T2D were assessed for changes in plasma glucagon levels following a single dose of dapagliflozin during experiments with stable versus falling plasma glucose. Changes in glucagon levels could largely be explained by changes in glucose levels.

In conclusion, SGLT2 inhibition can lower body weight and cardiovascular risk factors in obese patients without diabetes when combined with GLP-1RA, and it can reduce liver fat in T2D patients, in particular when given together with OM-3CA. SGLT2i effects on glucagon secretion can largely be explained by lower glucose levels rather than direct α-cell effects.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. p. 66
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1534
Keywords
SGLT2 inhibition, GLP-1 receptor agonism, DPP4 inhibition, NAFLD, prediabetes, type 2 diabetes, obesity, metabolic syndrome, glucagon.
National Category
Medical and Health Sciences
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-373522 (URN)978-91-513-0561-5 (ISBN)
Public defence
2019-03-08, Enghoff lecture-hall, Entrance 50, Uppsala academic hospital, Uppsala, 13:15 (English)
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AstraZeneca
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Available from: 2019-02-13 Created: 2019-01-20 Last updated: 2019-02-18

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Lundkvist, PerPereira, Maria J.Kamble, Prasad G.Katsogiannos, PetrosEriksson, Jan W.

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