Diabetic Ketoacidosis in Patients with Maturity-Onset Diabetes of the Young

Abstract

Maturity-onset diabetes of the young (MODY) is the most frequent monogenetic diabetes form. It is caused by mutations in genes important for the development and function of pancreatic beta-cells, resulting in impaired insulin secretion capacity. Up to now, 14 different types have been described. The inheritance pattern is autosomal dominant, leading to a strong family history with more than three affected generations. Young age at diagnosis and lack of pancreatic autoantibodies are further characteristics of MODY. The presence of diabetic ketoacidosis (DKA) was long regarded as an exclusion criterion for MODY. However, in recent years, several case reports on MODY patients presenting with DKA have been published. The present study aimed to give an overview of the current knowledge of DKA in MODY patients, with a collection of published case studies as a prerequisite for this review.

Keywords

DKA, ketosis - MODY - HNF4A - HNF1A - HNF1B - NEUROD1 - CEL - PAX4 - INS - ABCC8 - KCNJ11

Introduction

Worldwide, more than 500 million people are affected by diabetes [1]. In more than 90% of cases, patients suffer from type 2 diabetes and in about 5% of cases, type 1 diabetes. Other rarer diabetes types comprise monogenetic diabetes forms, such as maturity-onset diabetes of the young (MODY). MODY is caused by mutations in genes important for the development or function of pancreatic β-cells, resulting in impaired insulin secretion capacity. The pattern of inheritance is autosomal dominant. Currently, 14 MODY types, are known with HNF4A-MODY, GCK-MODY, HNF1A-MODY, and HNF1B-MODY being the most frequent variants ([Table 1]) [2]. MODY is diagnosed by genetic testing. Clinical findings suggesting the diagnosis of MODY comprise young age at disease manifestation, positive family history affecting more than three generations, diabetes without typical signs of type 1 or type 2 diabetes (negative pancreatic autoantibodies, no obesity, lack of other metabolic characteristics), and absence of diabetic ketoacidosis (DKA) [3]. Evaluation of DKA as an exclusion criterion was based on the assumption that even noncompliant patients never develop DKA because the remaining insulin production suppresses ketogenesis [4]. In contrast to this assumption, in recent years, several case reports have been published describing DKA in MODY patients. Furthermore, in their initial characterisation of MODY patients in comparison to patients with type 1 diabetes, Tattersall and Fajans already described DKA in two MODY patients [5]. The present work aimed to provide an overview of published case reports of MODY patients presenting with DKA.

Table 1 Classification of MODY types (modified according to [2]).

MODY type	Frequency	Gene affected	Age at manifestation	Clinical signs and symptoms	Treatment
HNF4A-MODY (formerly MODY-1)	5–10%	HNF4A	adolescence/early adulthood	frequent transient neonatal hyperinsulinaemic hypoglycaemia, progressive insulin secretory defect, severe progressive hyperglycaemia	diet, sulphonylureas, insulin
GCK-MODY (formerly MODY-2)	30–60%	GCK	from birth	stable, mild hyperglycaemia, typically asymptomatic, diagnosis often incidental	diet, exercise, possibly insulin during pregnancy
HNF1A-MODY (formerly MODY-3)	30–65%	HNF1A	adolescence/early adulthood	occasional transient neonatal hyperinsulinaemic hypoglycaemia, progressive insulin secretory defect, pronounced severe progressive hyperglycaemia, glucosuria	diet, sulphonylureas, insulin
PDX1-MODY (formerly MODY-4)	1%	PDX1	early adulthood	usually mild hyperglycaemia, sometimes overweight	diet, oral glucose-lowering drugs, insulin
HNF1B-MODY (formerly MODY-5)	<5%	HNF1B	adulthood	pronounced hyperglycaemia, presence of renal cysts and abnormalities of the urogenital tract, pancreatic hypoplasia	diet, oral glucose-lowering drugs, insulin
NEUROD1-MODY (formerly MODY-6)	<1%	NEUROD1	early adulthood	variable symptoms, sometimes overweight	oral glucose-lowering drugs, insulin
KLF11-MODY (formerly MODY-7)	<1%	KLF11	early adulthood	rare, therefore, no information possible	oral glucose-lowering drugs, insulin
CEL-MODY (formerly MODY-8)	<1%	CEL	early adulthood	associated with exocrine pancreatic insufficiency	oral glucose-lowering drugs, insulin
PAX4-MODY (formerly MODY-9)	<1%	PAX4	early adulthood	rare, therefore, no information possible	diet, oral glucose-lowering drugs, insulin
INS-MODY (formerly MODY-10)	<1%	INS	hardly any information possible	hardly any information possible, variable symptoms	diet, oral glucose-lowering drugs, insulin
BLK-MODY (formerly MODY-11)	<1%	BLK	rare, therefore, no information possible	rare, therefore, no information possible	diet, oral glucose-lowering drugs, insulin
ABCC8-MODY (formerly MODY-12)	<1%	ABCC8		phenotype similar to HNF4A-MODY and HNF1A-MODY	diet, sulphonylureas
KCNJ11-MODY (formerly MODY-13)	<1%	KCNJ11		phenotype similar to HNF4A-MODY and HNF1A-MODY	diet, sulphonylureas
APPL1-MODY (formerly MODY-14)	<1%	APPL1	rare, therefore, no information possible	rare, therefore, no information possible	diet, oral glucose-lowering drugs, insulin

ABCC8, ATP-binding cassette transporter subfamily C member 8; APPL1, Adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1; BLK, B-Lymphocyte specific kinase; CEL, Carboxylester lipase; GCK, Glukokinase; HNF1A, Hepatic nuclear factor 1α; HNF4A, Hepatic nuclear factor 4α; HNF1B, Hepatic nuclear factor 1β; INS, Insulin; KCNJ11, Potassium Inwardly Rectifying Channel Subfamily J Member 11; KLF11, Kruppel-like factor 11; MODY, maturity-onset diabetes of the young; NEUROD1, Neuronal Differentiation 1; PAX4, Paired Box 4; PDX1, Pancreas/duodenum homeonbox protein-1.

Materials and Methods

PubMed database was searched until 22^nd April 2024. The search terms “(maturity-onset diabetes of the young) AND (ketoacidosis)” were used. Only case reports or case series written in English language were considered. Patients with positive pancreatic autoantibodies were excluded. Subsequently, the included references were manually screened for relevant articles ([Fig. 1]). This research revealed 21 cases [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21]. A case report we have recently published was added to the analysis [22].

Results

In total, 22 MODY patients with DKA or diabetic ketosis (DK) were analysed ([Table 2] and [Table 3]), comprising nine different MODY types, HNF4A-MODY (formerly MODY-1), HNF1A-MODY (formerly MODY-3), HNF1B-MODY (formerly MODY-5), NEUROD1-MODY (formerly MODY-6), CEL-MODY (formerly MODY-8), PAX4-MODY (formerly MODY-9), INS-MODY (formerly MODY-10), ABCC8-MODY (formerly MODY-12), and KCNJ11 (formerly MODY-13). In one patient, family history pointed to MODY diagnosis; however, genetic testing was not performed. In the majority of cases (n=15), female patients were affected, and only seven patients were male. The mean age at the presentation with DKA or DK was 19 years and the mean age at diagnosis was 15 years. The mean body mass index (BMI), which was given in thirteen cases, was 20.6 kg/m². Treatment comprised insulin (n=7), alpha glucosidase inhibitor (n=2), sodium-dependent glucose co-transporter 2 (SGLT-2) inhibitor (n=1), or sulfonylurea (n=1), whereas eleven patients received no treatment at presentation with DKA or DK. DKA or DK were the initial manifestation of diabetes, alone (n=10) or in combination with pneumonia (n=1), whereas nonadherence, alone (n=7) or in combination with alcohol consumption (n=1) or infection (n=1), and SGLT2 inhibitor treatment in the presence of ketogenic diet (n=1) were reported as potential causes of the metabolic derangement. In one patient, the cause remained unknown. Clinical signs and symptoms were reported in 17 patients and comprised mental alterations (n=6), weakness (n=6), vomiting (n=6), signs of dehydration, including dry mouth (n=5), thirst/polydipsia (n=5), polyuria (n=4), weight loss (n=3), hunger/polyphagia (n=2), abdominal pain (n=2), loss of appetite (n=1), muscle pain (n=1), tachycardia (n=1), nausea (n=1), severe wheezing (n=1), stuffed nose (n=1), sleep snoring (n=1), and skin lesions (n=1). Glucose concentrations, with a mean value of 27.2 mmol/L (490 mg/dL), were reported in 15 patients. HbA1c was given in 15 patients, and the mean HbA1c was 14.1% (130.6 mmol/mol). Pancreatic antibody negativity was reported in 19 patients, whereas it was not mentioned in three patients. pH (n=9), base excess (n=6), and bicarbonate (n=4) were reported in a limited number of patients, with mean values of 7.20, −14.3 mmol/L, and 18.5 mmol/L, respectively. Insulin secretion parameters were reported in 16 patients and insulin secretion capacity was decreased in nine patients and normal in seven patients. DKA was documented in 16 patients and DK in 6 patients suffering from HNF1A-MODY, HNF1B-MODY, NEUROD1-MODY, and ABCC8-MODY.

Table 2 Clinical characteristics of MODY patients with diabetic ketoacidosis or ketosis.

Reference	MODY type	Sex	Age (yrs)	Age at diagnosis (yrs)	BMI (kg/m2)	Treatment	Cause of DKA	Clinical signs
Harms M et al. [22]	HNF4A (MODY-1)	f	27	10	29.2	insulin	discontinuation of insulin therapy, soft tissue infection	weakness, loss of appetite, vomiting
Pruhova S et al. [6]	HNF1A (MODY-3)	f	17	4	20.1	insulin	nonadherence, alcohol consumption	recurrent vomiting, lethargy, dehydration
Pruhova S et al. [6]	HNF1A (MODY-3)	m	23	13	29.4	insulin	nonadherence	recurrent vomiting, unconsciousness, dehydration, tachycardia due to atrial flutter
Egan AM et al. [7]	HNF1A (MODY-3)	f	20	12	n. a.	insulin	nonadherence	n. a.
Tang J et al. [8]	HNF1A (MODY-3)	f	21	18	16.5	sulfonylurea	discontinuation of medication for 3 months	dizziness,vomiting and abdominal pain
Phan F et al. [9]	HNF1A (MODY-3)	f	25	14	23.8	dapagliflozin	SGLT2i, ketogenic diet	progressive asthenia, body weakness, impaired concentration and attention, diffuse muscle pain
Motyka R et al. [10]	HNF1B (MODY-5)	m	33	33	n. a.	none	initial diagnosis	polyuria, polydipsia, polyphagia, and weightloss of 20 kg in 3 months
Cheng Y et al. [11]	HNF1B (MODY-5)	f	21	20	13.9	acarbose	discontinuation of medication	coma
Hayakawa-Iwamoto A et al. [12]	HNF1B (MODY-5)	m	34	34	16.3	none	initial diagnosis	dry mouth, weight loss of 10 kg within 1 yr
Ge S et al. [13]	HNF1B (MODY-5)	f	26	26	15.5	none	initial diagnosis	thirst, easy hunger and polyuria for half a yr
Xin S & Zhang X [14]	HNF1B (MODY-5)	m	28	28	16.3	insulin	nonadherence	intermittent nausea and vomiting
Horikawa Y et al. [15]	NEUROD1 (MODY-6)	f	15	14	n. a.	alpha-glucosidase inhibitor	unknown cause	n. a.
Horikawa Y et al. [15]	NEUROD1 (MODY-6)	f	11	11	n. a.	none	initial diagnosis	general malaise, vomiting
Horikawa Y et al. [15]	NEUROD1 (MODY-6)	f	20	10	n. a.	insulin	avoidance of insulin injections for more than 1 yr	n. a.
Horikawa Y et al. [15]	NEUROD1 (MODY-6)	f	12	12	n. a.	none	initial diagnosis	n. a.
Kondoh T et al. [16]	CEL (MODY-8)	f	13	13	24.8	none	initial diagnosis	nausea, epigastric pain, unconsciousness
Zhang D et al. [17]	PAX4 (MODY-9)	m	1.6	1.6	n. a.	none	initial diagnosis, pneumonia	polyuria and polydipsia for half a month, severe wheezing for 2 days, poor general condition, decreased level of consciousness
Johnson SR et al. [18]	INS (MODY-10)	f	11	11	n. a.	none	initial diagnosis	n. a.
Li J et al. [19]	ABCC8 (MODY-12)	f	8	8	14.0	none	initial diagnosis	stuffed nose and sleep snoring
Li J et al. [19]	ABCC8 (MODY12)	m	25	25	27.8	none	initial diagnosis	dry mouth, polydipsia, polyuria, and fatigue
Chen C et al. [20]	KCNJ11 (MODY13)	m	9	9	n. a.	none	initial diagnosis	two-week history of dry mouth and polydipsia and weight loss of 9 kg in a month
Kadota-Shinozaki A et al. [21]	unknown	f	19	11	20.0	insulin	discontinuation of insulin injection for 2 yrs	general malaise, eruption spread over her chest

ABCC8, gene coding for ATP-binding cassette transporter sub-family C member 8; BMI, body mass index; CEL, gene coding for carboxyl-ester lipase; DKA, diabetic ketoacidosis; f, female; HNF1A, gene coding for hepatocyte nuclear factor 1α; HNF1B, gene coding for hepatocyte nuclear factor 1β; HNF4A, gene coding for hepatocyte nuclear factor 4α; INS, gene coding for insulin; KCNJ11, gene coding for potassium inwardly-rectifying channel subfamily J member 11; m, male; MODY, maturity-onset diabetes of the young; n. a., not available; NEUROD1, gene coding for neurogenic differentiation 1; PAX4, gene coding for paired box 4; SGLT2i, sodium-dependent glucose co-transporter 2 inhibitor; yr, year.

Table 3 Laboratory parameters of MODY patients with diabetic ketoacidosis or ketosis.

Reference	Mutation	Glucose (mmol/L [mg/dL])	HbA1c (% [mmol/mol])	Pancreatic auto-antibodies	pH	Base excess (mmol/L)	Bicarbonate (mmol/L)	Insulin secretion capacity	Further results
Harms M et al. [22]	c.970 C>T (p.R324C; pArg324Cys) in HNF4A	40.7 [734]	14.1 [130.6]	negative	7.01	−23.5	5.5	normal insulin secretion capacity	DKA
Pruhova S et al. [6]	p.Arg272His in HNF1A	97 [1748]	15 [140]	negative	6.80	−33	n. a.	n. a.	DKA, acute renal failure
Pruhova S et al. [6]	p.Ser142Phe in HNF1A	34 [613]	13 [119]	negative	7.03	−14	n. a.	n. a.	DKA, acute renal failure
Egan AM et al. [7]	c.391 C>T, pArg131Trp in HNF1A	n. a.	13.1 [120]	negative	n. a.	n. a.	n. a.	detectable C-peptide	DKA
Tang J et al. [8]	c.779 C>T, p.T260M in HNF1A	11.8 [213]	n. a.	negative	n. a.	n. a.	n. a.	low normal fasting C-peptide and sufficient postprandial increase	DK, urine ketones 100 mg/dL (Normal:<80)
Phan F et al. [9]	HNF1A (mutation not given)	8.9 [161]	n. a.	n. a.	7.41	n. a.	n. a.	n. a.	euglycaemic DK, blood ketones 3.8 mmol/L
Motyka R et al. [10]	17q12 deletion including HNF1B	33.3 [600]	20.7 [202.7]	negative	n. a.	n. a.	n. a.	decreased fasting C-peptide	DKA
Cheng Y et al. [11]	17q12 deletion including HNF1B	n. a.	n. a.	negative	n. a.	n. a.	n. a.	n. a.	DKA
Hayakawa-Iwamoto A et al. [12]	HNF1B deletion	32.8 [591]	19.4 [189]	negative	7.48	11.3	36.7	low urinary C-peptide secretion	DK, total ketone bodies 1.016 mmol/L
Ge S et al. [13]	c.826 C>T, p.Arg276* in HNF1B	28.9 [521]	17.4 [166.7]	negative	n. a.	n. a.	n. a.	insufficient insulin secretion	DKA
Xin S & Zhang X [14]	17q12 deletion including HNF1B	21.4 [386]	11.2 [98.9]	negative	7.37	n. a.	n. a.	low fasting and postprandrial serum C-peptide levels	DK, urine ketones 3+
Horikawa Y et al. [15]	c.616_617insC, p.(His206ProfsTer38) in NEUROD1	n. a.	n. a.	negative	n. a.	n. a.	n. a.	no absolute insulin deficiency, but reduced insulin secretory capacity at glucagon load test	DKA
Horikawa Y et al. [15]	c.734delC.p.(Pro245ArgfsTer17) in NEUROD1	n. a.	n. a.	negative	n. a.	n. a.	n. a.	normal insulin secretion at glucagon load test	DKA
Horikawa Y et al. [15]	c.470 T>G, p.(Leu157Arg) in NEUROD1	n. a.	n. a.	n. a.	n. a.	n. a.	n. a.	n. a.	DKA
Horikawa Y et al. [15]	c.616delC, p.(His206ThrfsTer56) in NEUROD1	n. a.	10.7 [93]	n. a.	n. a.	n. a.	n. a.	n. a.	DK, urine ketone body positivity
Kondoh T et al. [16]	p.Ser49CysfsTer52 in CEL	n. a.	n. a.	negative	n. a.	n. a.	n. a.	extremely low C-peptide level	DKA
Zhang D et al. [17]	c.487 C>T, R163W in PAX4	20.74 [374]	11.1 [97.8]	negative	7.07	−23.5	n. a.	decreased fasting insulin and C-peptide levels	DKA, urine ketones 3+
Johnson SR et al. [18]	c.277 G>A, p.Glu93Lys in INS	15 [270]	15.2 [142.6]	negative	7.25	n. a.	11	low fasting C-peptide	mild DKA
Li J et al. [19]	c.1555 C>T, p.R519C in ABCC8	18.81 [339]	12.8 [116.4]	negative	n. a.	n. a.	n. a.	normal fasting C-peptide	DK, urine ketones 1+
Li J et al. [19]	c.2885 C>T, p.S962L in ABCC8	13.52 [244]	11.2 [98.9]	negative	n. a.	n. a.	n. a.	low normal fasting C-peptide	DKA, urine ketones 3+
Chen C et al. [20]	c.843 C>T, p.L281=in KCNJ11	21.5 [387]	9.9 [84.7]	negative	n. a.	n. a.	n. a.	sufficient insulin increase, but insufficient C-peptide increase in the standard meal test	DKA, urine ketones 3+
Kadota-Shinozaki A et al. [21]	Genetic testing not done	24.6 [443]	16.7 [159.0]	negative	7.395	−2.8	20.7	preserved insulin secretory capacity in glucagon test	mild DKA, 3-hydroxybutyrate 3908 µmol/L, acetoacetate 1575 µmol/L triglycerides 3386 mg/dL, total cholesterol 638 mg/dL

ABCC8, gene coding for ATP-binding cassette transporter sub-family C member 8; CEL, gene coding for carboxyl-ester lipase; DK, diabetic ketosis; DKA, diabetic ketoacidosis; HNF1A, gene coding for hepatocyte nuclear factor 1α; HNF1B, gene coding for hepatocyte nuclear factor 1β; HNF4A, gene coding for hepatocyte nuclear factor 4α; INS, gene coding for insulin; KCNJ11, gene coding for potassium inwardly-rectifying channel subfamily J member 11; MODY, maturity-onset diabetes of the young; n. a., not available; NEUROD1, gene coding for neurogenic differentiation 1; PAX4, gene coding for paired box 4.

Conclusions

It is worth noting that DKA and DK occurred preferentially in MODY forms, which are characterised by a more severe clinical course. No case of DKA or DK was documented in a patient with GCK-MODY, typically associated with only moderately elevated glucose concentrations and the absence of diabetes complications [23]. In contrast, after initial treatment with sulfonylureas, about 40% of patients with HNF1A- and HNF4A-MODY require insulin treatment in the further course. Furthermore, due to the progressive nature of these MODY forms, patients regularly develop microvascular and macrovascular complications [24] [25].

The growing awareness that people with MODY can develop DK, albeit rarely, has been recognised in the latest ISPAD Clinical Practice Consensus Guidelines on the diagnosis and management of monogenic diabetes in children and adolescents [26]. Nevertheless, other guidelines continue to cite DKA as an exclusion criterion for MODY diagnosis [27]. These recommendations need to be revised accordingly. In light of the potential occurrence of DKA at diagnosis as well as in the further course of the disease, the affected patients should be trained accordingly, given that DKA is still associated with increased mortality [28].

Conflict of Interest

The author declares that he has no conflict of interest.

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Publication History

Received: 25 April 2024

Accepted after revision: 30 May 2024

Accepted Manuscript online:
05 June 2024

Article published online:
28 June 2024