Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Endocrine
Published in: Endocrine 2/2017

Open Access 01-08-2017 | Original Article

A single dose of dapagliflozin, an SGLT-2 inhibitor, induces higher glycosuria in GCK- and HNF1A-MODY than in type 2 diabetes mellitus

Authors: J. Hohendorff, M. Szopa, J. Skupien, M. Kapusta, B. Zapala, T. Platek, S. Mrozinska, T. Parpan, W. Glodzik, A. Ludwig-Galezowska, B. Kiec-Wilk, T. Klupa, M. T. Malecki

Published in: Endocrine | Issue 2/2017

Login to get access

Abstract

Aims

SGLT2 inhibitors are a new class of oral hypoglycemic agents used in type 2 diabetes (T2DM). Their effectiveness in maturity onset diabetes of the young (MODY) is unknown. We aimed to assess the response to a single dose of 10 mg dapagliflozin in patients with Hepatocyte Nuclear Factor 1 Alpha (HNF1A)-MODY, Glucokinase (GCK)-MODY, and type 2 diabetes.

Methods

We examined 14 HNF1A-MODY, 19 GCK-MODY, and 12 type 2 diabetes patients. All studied individuals received a single morning dose of 10 mg of dapagliflozin added to their current therapy of diabetes. To assess the response to dapagliflozin we analyzed change in urinary glucose to creatinine ratio and serum 1,5-Anhydroglucitol (1,5-AG) level.

Results

There were only four patients with positive urine glucose before dapagliflozin administration (one with HNF1A-MODY, two with GCK-MODY, and one with T2DM), whereas after SGLT-2 inhibitor use, glycosuria occurred in all studied participants. Considerable changes in mean glucose to creatinine ratio after dapagliflozin administration were observed in all three groups (20.51 ± 12.08, 23.19 ± 8.10, and 9.84 ± 6.68 mmol/mmol for HNF1A-MODY, GCK-MODY, and T2DM, respectively, p < 0.001 for all comparisons). Post-hoc analysis revealed significant differences in mean glucose to creatinine ratio change between type 2 diabetes and each monogenic diabetes in response to dapagliflozin (p = 0.02, p = 0.003 for HNF1-A and GCK MODY, respectively), but not between the two MODY forms (p = 0.7231). Significant change in serum 1,5-AG was noticed only in T2DM and it was −6.57 ± 7.34 mg/ml (p = 0.04).

Conclusions

A single dose of dapagliflozin, an SGLT-2 inhibitor, induces higher glycosuria in GCK- and HNF1A-MODY than in T2DM. Whether flozins are a valid therapeutic option in these forms of MODY requires long-term clinical studies.
Literature
1.
B.M. Shields, S. Hicks, M.H. Shepherd, K. Colclough, A.T. Hattersley, S. Ellard, Maturity-onset diabetes of the young (MODY): how many cases are we missing? Diabetologia 53(12), 2504–2508 (2010)CrossRefPubMed
2.
A. Stride, A.T. Hattersley, Different genes, different diabetes: lessons from maturity-onset diabetes of the young. Ann. Med. 34(3), 207–216 (2002)CrossRefPubMed
3.
J. Kropff, M.P. Selwood, M.I. McCarthy, A.J. Farmer, K.R. Owen, Prevalence of monogenic diabetes in young adults: a community-based, cross-sectional study in oxfordshire, UK. Diabetologia 54(5), 1261–1263 (2011)CrossRefPubMed
4.
K. Yamagata, Roles of HNF1α and HNF4α in pancreatic β-cells: lessons from a monogenic form of diabetes (MODY). Vitam. Horm. 95, 407–423 (2014)CrossRefPubMed
5.
M. Szopa, J. Wolkow, B. Matejko, J. Skupien, T. Klupa, I. Wybranska, I. Trznadel-Morawska, B. Kiec-Wilk, M. Borowiec, M.T. Malecki, Prevalence of retinopathy in adult patients with GCK-MODY and HNF1A-MODY. Exp. Clin. Endocrinol. Diabetes 123(9), 524–528 (2015)CrossRefPubMed
6.
B. Isomaa, M. Henricsson, M. Lehto, C. Forsblom, S. Karanko, L. Sarelin, M. Häggblom, L. Groop, Chronic diabetic complications in patients with MODY3 diabetes. Diabetologia 41(4), 467–473 (1998)CrossRefPubMed
7.
E.R. Pearson, B.J. Starkey, R.J. Powell, F.M. Gribble, P.M. Clark, A.T. Hattersley, Genetic cause of hyperglycaemia and response to treatment in diabetes. Lancet 362(9392), 1275–1281 (2003)CrossRefPubMed
8.
M. Shepherd, B. Shields, S. Ellard, O. Rubio-Cabezas, A.T. Hattersley, A genetic diagnosis of HNF1A diabetes alters treatment and improves glycaemic control in the majority of insulin-treated patients. Diabet. Med. 26(4), 437–441 (2009)CrossRefPubMed
9.
T.J. McDonald, S. Ellard, Maturity onset diabetes of the young: identification and diagnosis. Ann. Clin. Biochem. 50(5), 403–415 (2013)CrossRefPubMed
10.
M. Pontoglio, D. Prié, C. Cheret, A. Doyen, C. Leroy, P. Froguel, G. Velho, M. Yaniv, G. Friedlander, HNF1alpha controls renal glucose reabsorption in mouse and man. EMBO. Rep. 1(4), 359–365 (2000)CrossRefPubMedPubMedCentral
11.
A.J. Chakera, A.M. Steele, A.L. Gloyn, M.H. Shepherd, B. Shields, S. Ellard, A.T. Hattersley, Recognition and management of individuals with hyperglycemia because of a heterozygous glucokinase mutation. Diabetes Care 38(7), 1383–1392 (2015)CrossRefPubMed
12.
A.M. Steele, B.M. Shields, K.J. Wensley, K. Colclough, S. Ellard, A.T. Hattersley, Prevalence of vascular complications among patients with glucokinase mutations and prolonged, mild hyperglycemia. JAMA 311(3), 279–286 (2014)CrossRefPubMed
13.
M. Szopa, G. Osmenda, G. Wilk, B. Matejko, J. Skupien, B. Zapala, W. Mlynarski, T. Guzik, M.T. Malecki, Intima-media thickness and endothelial dysfunction in GCK and HNF1A-MODY patients. Eur. J. Endocrinol. 172(3), 277–283 (2015)CrossRefPubMed
14.
A. Stride, B. Shields, O. Gill-Carey, A.J. Chakera, K. Colclough, S. Ellard, A.T. Hattersley, Cross-sectional and longitudinal studies suggest pharmacological treatment used in patients with glucokinase mutations does not alter glycaemia. Diabetologia 57(1), 54–56 (2014)CrossRefPubMed
15.
E. Guenat, G. Seematter, J. Philippe, E. Temler, E. Jequier, L. Tappy, Counterregulatory responses to hypoglycemia in patients with glucokinase gene mutations. Diabetes Metab. 26(5), 377–384 (2000)PubMed
16.
M. Szopa, A. Ludwig-Galezowska, P. Radkowski, J. Skupien, B. Zapala, T. Platek, T. Klupa, B. Kiec-Wilk, M. Borowiec, W. Mlynarski, P. Wolkow, M.T. Malecki, Genetic testing for monogenic diabetes using targeted next-generation sequencing in patients with maturity-onset diabetes of the young. Pol. Arch. Med. Wewn. 125(11), 845–851 (2015)PubMed
17.
S. Ellard, H. Lango Allen, E. De Franco, S.E. Flanagan, G. Hysenaj, K. Colclough, J.A. Houghton, M. Shepherd, A.T. Hattersley, M.N. Weedon, R. Caswell, Improved genetic testing for monogenic diabetes using targeted next-generation sequencing. Diabetologia 56(9), 1958–1963 (2013)CrossRefPubMedPubMedCentral
18.
M.A. Abdul-Ghani, L. Norton, R.A. DeFronzo, Efficacy and safety of SGLT2 inhibitors in the treatment of type 2 diabetes mellitus. Curr. Diab. Rep. 12(3), 230–238 (2012)CrossRefPubMed
19.
B. Komoroski, N. Vachharajani, D. Boulton, D. Kornhauser, M. Geraldes, L. Li, M. Pfister, Dapagliflozin, a novel SGLT2 inhibitor, induces dose-dependent glucosuria in healthy subjects. Clin. Pharmacol. Ther. 85(5), 520–526 (2009)CrossRefPubMed
20.
B. Komoroski, N. Vachharajani, Y. Feng, L. Li, D. Kornhauser, M. Pfister, Dapagliflozin, a novel, selective SGLT2 inhibitor, improved glycemic control over 2 weeks in patients with type 2 diabetes mellitus. Clin. Pharmacol. Ther. 85(5), 513–519 (2009)CrossRefPubMed
21.
J.B. McGill, T.G. Cole, W. Nowatzke, S. Houghton, E.B. Ammirati, T. Gautille, M.J. Sarno, Circulating 1,5-anhydroglucitol levels in adult patients with diabetes reflect longitudinal changes of glycemia: a U.S. trial of the GlycoMark assay. Diabetes Care 27(8), 1859–1865 (2004)CrossRefPubMed
22.
K.M. Dungan, J.B. Buse, J. Largay, M.M. Kelly, E.A. Button, S. Kato, S. Wittlin, 1,5-anhydroglucitol and postprandial hyperglycemia as measured by continuous glucose monitoring system in moderately controlled patients with diabetes. Diabetes Care 29(6), 1214–1219 (2006)CrossRefPubMed
23.
E.S. Kilpatrick, B.G. Keevilt, K.L. Richmond, P. Newland, G.M. Addison, Plasma 1,5-anhydroglucitol concentrations are influenced by variations in the renal threshold for glucose. Diabet. Med. 16(6), 496–499 (1999)CrossRefPubMed
24.
J. Skupien, S. Gorczynska-Kosiorz, T. Klupa, K. Wanic, E.A. Button, J. Sieradzki, M.T. Malecki, Clinical application of 1,5-anhydroglucitol measurements in patients with hepatocyte nuclear factor-1alpha maturity-onset diabetes of the young. Diabetes Care 31(8), 1496–1501 (2008)CrossRefPubMedPubMedCentral
25.
M. Szopa, M. Kapusta, B. Matejko, T. Klupa, T. Koblik, B. Kiec-Wilk, M. Borowiec, M.T. Malecki, Comparison of glomerular filtration rate estimation from serum creatinine and cystatin C in HNF1A-MODY and other types of diabetes. J. Diabetes Res. (2015). doi:10.​1155/​2015/​183094
26.
E.R. DeLong, D.M. DeLong, D.L. Clarke-Pearson, Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics 44(3), 837–845 (1988)CrossRefPubMed
27.
2016 Guidelines on the management of diabetic patients, A position of diabetes Poland. Clin. Diabet. 5(Suppl. A), A16–A18 (2016)
28.
S.E. Inzucchi, R.M. Bergenstal, J.B. Buse, M. Diamant, E. Ferrannini, M. Nauck, A.L. Peters, A. Tsapas, R. Wender, D.R. Matthew, Management of hyperglycaemia in type 2 diabetes, 2015: a patient-centred approach. Update to a Position Statement of the American Diabetes Association and the European Association for the Study of DiabetesDiabetologia 58, 429–442 (2015).CrossRefPubMed
29.
B. Zinman, C. Wanner, J.M. Lachin, D. Fitchett, E. Bluhmki, S. Hantel, M. Mattheus, T. Devins, O.E. Johansen, H.J. Woerle, U.C. Broedl, S.E. Inzucchi, EMPA-REG OUTCOME investigators: Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N. Engl. J. Med. 373(22), 2117–2128 (2015)CrossRefPubMed
30.
R.P. Monica Reddy, S.E. Inzucchi, SGLT2 inhibitors in the management of type 2 diabetes. Endocrine 53(2), 364–372 (2016)CrossRefPubMed
31.
R.A. DeFronzo, M. Hompesch, S. Kasichayanula, X. Liu, Y. Hong, M. Pfister, L.A. Morrow, B.R. Leslie, D.W. Boulton, A. Ching, F.P. LaCreta, S.C. Griffen, Characterization of renal glucose reabsorption in response to dapagliflozin in healthy subjects and subjects with type 2 diabetes. Diabetes. Care 36(10), 3169–3176 (2013)CrossRefPubMedPubMedCentral
32.
A.K. Ovsyannikova, O.D. Rymar, E.V. Shakhtshneider, V.V. Klimontov, E.A. Koroleva, N.E. Myakina, M.I. Voevoda, ABCC8-related maturity-onset diabetes of the young (MODY12): clinical features and treatment perspective. Diabetes Ther. 7(3), 591–600 (2016)CrossRefPubMedPubMedCentral
33.
J.J. Liu, T. Lee, R.A. DeFronzo, Why do SGLT2 inhibitors inhibit only 30-50% of renal glucose reabsorption in humans? Diabetes 61(9), 2199–2204 (2012)CrossRefPubMed
34.
M.A. Abdul-Ghani, R.A. DeFronzo, L. Norton, Novel hypothesis to explain why SGLT2 inhibitors inhibit only 30–50% of filtered glucose load in humans. Diabetes 62(10), 3324–3328 (2013)CrossRefPubMedPubMedCentral
35.
V. Vallon, S.C. Thomson, Targeting renal glucose reabsorption to treat hyperglycaemia: the pleiotropic effects of SGLT2 inhibition. Diabetologia 60(2), 215–225 (2017)CrossRefPubMed
36.
J.B. Buse, J.L. Freeman, S.V. Edelman, L. Jovanovic, J.B. McGill, Serum 1,5-anhydroglucitol (GlycoMark): a short-term glycemic marker. Diabetes. Technol. Ther. 5(3), 355–363 (2003)CrossRefPubMed
37.
A. Pal, A.J. Farmer, C. Dudley, M.P. Selwood, B.A. Barrow, R. Klyne, J.P. Grew, M.I. McCarthy, A.L. Gloyn, K.R. Owen, Evaluation of serum 1,5 anhydroglucitol levels as a clinical test to differentiate subtypes of diabetes. Diabetes Care 33(2), 252–257 (2010)CrossRefPubMedPubMedCentral
38.
S.A. Mughal, R. Park, N. Nowak, A.L. Gloyn, F. Karpe, H. Matile, M.T. Malecki, M.I. McCarthy, M. Stoffel, K.R. Owen, Apolipoprotein M can discriminate HNF1A–MODY from type 1 diabetes. Diabet. Med. 30(2), 246–250 (2013)CrossRefPubMedPubMedCentral
39.
G. Thanabalasingham, N. Shah, M. Vaxillaire, T. Hansen, T. Tuomi et al.. A large multi-centreeuropean study validates high-sensitivity C-reactive protein (hsCRP) as a clinical biomarker for the diagnosis of diabetes subtypes. Diabetologia 54(11), 2801–2810 (2011)CrossRefPubMed
40.
N. Nowak, J. Hohendorff, I. Solecka, M. Szopa, J. Skupien, B. Kiec-Wilk, W. Mlynarski, M.T. Malecki, Circulating ghrelin level is higher in HNF1A-MODY and GCK-MODY than in polygenic forms of diabetes mellitus. Endocrine 50(3), 643–649 (2015)CrossRefPubMedPubMedCentral
41.
H. Qiu, A. Novikov, V. Vallon, Ketosis and diabetic ketoacidosis in response to SGLT2 inhibitors: basic mechanisms and therapeutic perspectives. Diabetes Metab. Res. Rev. (2017). doi:10.​1002/​dmrr.​2886 [Epub ahead of print]
42.
S. Pruhova, P. Dusatkova, D. Neumann, E. Hollay, O. Cinek, J. Lebl, Z. Sumnik, Two cases of diabetic ketoacidosis in HNF1A-MODY linked to severe dehydration: is it time to change the diagnostic criteria for MODY? Diabetes Care 36(9), 2573–2574 (2013)CrossRefPubMedPubMedCentral
43.
Egan A.M., Cunningham A., Jafar-Mohammadi B., Dunne F.P., Diabetic ketoacidosis in the setting of HNF1A-maturity onset diabetes of the young. BMJ Case Reports. (2015). doi:10.​1136/​bcr-2014-209163
Metadata
Title
A single dose of dapagliflozin, an SGLT-2 inhibitor, induces higher glycosuria in GCK- and HNF1A-MODY than in type 2 diabetes mellitus
Authors
J. Hohendorff
M. Szopa
J. Skupien
M. Kapusta
B. Zapala
T. Platek
S. Mrozinska
T. Parpan
W. Glodzik
A. Ludwig-Galezowska
B. Kiec-Wilk
T. Klupa
M. T. Malecki
Publication date
01-08-2017
Publisher
Springer US
Published in
Endocrine / Issue 2/2017
Print ISSN: 1355-008X
Electronic ISSN: 1559-0100
DOI
https://doi.org/10.1007/s12020-017-1341-2

Other articles of this Issue 2/2017

Endocrine 2/2017 Go to the issue

Original Article

Ultrasonographic prediction of highly aggressive telomerase reverse transcriptase (TERT) promoter-mutated papillary thyroid cancer

Original Article

Calcium levels on admission and before discharge are associated with mortality risk in hospitalized patients

Original Article

Effect of aerobic interval training on serum IL-10, TNFα, and adipokines levels in women with multiple sclerosis: possible relations with fatigue and quality of life

Original Article

Causes of referral to the first endocrine visit of patients with thyroid carcinoma in a mildly iodine-deficient area

Editorial

Craniopharyngiomas: a life-changing tumor

Editorial

Syndrome of inappropriate antidiuresis should it be managed by specialised endocrinologists?
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine
Image Credits