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Introduction

Recent evidence indicates that ketosis-prone diabetes mellitus (KPDM), which was once described as atypical diabetes mellitus, idiopathetic type 1 diabetes (type 1B diabetes) or flatbush diabetes, shows a 2- or 3-fold higher prevalence in men compared to women (1–5). Previous studies by our study group and other investigators indicate that the majority of patients with KPDM are obese, young and middle-aged patients with a strong family history of type 2 diabetes (2). Of note, KPDM is mostly observed in males. Although our understanding of the pathogenesis of diabetic ketoacidosis (DKA) is increasing, it remains unknown why obese male individuals are more prone to DKA (2). The male predominance of KPDM appears to be independent of the degree of obesity and age at presentation, even though the syndrome is strongly linked to obesity (2,3). Vital information is lacking to help identify the individuals at risk and to prevent or postpone the onset of DKA in patients with KPDM. Gender differences in KPDM and the role of gonadal hormones and other factors in modulating insulin sensitivity and glycometabolism are of increasing interest (6–8).

The male-to-female ratios of KPDM patients were 1.5:1 to 6:1 according to previous studies (2,9–12). In 1987, Winter et al (9) first systematically reported a small cohort of African-American adolescents with severe hyperglycemia and DKA, with a lack of any clear inducements. They specified this subtype of syndrome as atypical diabetes. In the past two or three decades, clinical presentations of the syndrome have been increasingly recognized worldwide. KPDM was recently reported in a non-Caucasian population, including Sub-Sahala-African or West African (3), Hispanic descent (10), Japanese (12) and Chinese populations (13,14). In 2004, Mauvais-Jarvis et al (3) published a 10-year longitudinal study of KPDM in immigrants from sub-Saharan-Africa who were living in Paris, France. They reported that >3 quarters of the patients with KPDM were male. The following year, Maldonado et al (14) reported a large, longitudinal, prospective study of multiethnic patients with four different subforms of KPDM according to the β-cell function and antibodies of patients in Texas. The male-to-female ratio in this study was 1.72:1. In Asia, the male predominance in patients with KDPM is more evident. Yamada and Nonaka (12) reported 8 Japanese adolescents who were all obese and had a soft-drink history. The syndrome was designated as ‘ketoacidosis-onset type 2 diabetes’ and ‘soft-drink diabetes’ (10). Investigators in Hong Kong and Taiwan reported that 8 of 11 (73%) and 28 of 40 (70%) cases were male patients, respectively (13,14). Consistent with prior studies regarding KPDM, a cohort of KPDM patients were characterized as male or female, and 96.7% of the individuals were male in one of our recent studies in Western China (2). The gender differences and occurrence of obesity in KPDM are shown in Table I.

Table I. Gender differences and obesity in ketosis-prone diabetes.

Table I.

Gender differences and obesity in ketosis-prone diabetes.

Parameters	Chengdu	Hong Kong	Taiwan	Tokyo	Paris	Atlanta	Houston	TX, CA and NY
Male KPDM, % (n/N)	96.7	72.7	70.0	100.0	75.6	63.6	55.6	75.6
	(29/30)	(8/11)	(28/40)	(8/8)	(115/152)	(49/77)	(59/106)	(115/152)
BMI, kg/m2	29.3±2.8	24.9±3.9	22.2	–	24.6±4.8	37±1.0	30.3±6.9	M: 27.9±5.6 F: 30.3±6.5
Obese, %	70.0	72.7	–	100.0	75.0	100.0	–	–
(Refs.)	(2)	(13)	(14)	(12)	(11)	(21)	(15)	(33)

[i] N, total number; BMI, body mass index; M, male; F, female; TX, Texas; CA, California; NY, New York.

The mechanisms of male predominance in KPDM are unknown. It is often assumed that there is little or no gender bias within either type 1 or type 2 diabetes mellitus. Recent studies have shown that male type 2 diabetic patients are prone to have unproved diabetic ketosis, particularly the overweight individuals. The potential triggers are complex and the underlying mechanisms of ketosis-prone in patients with KPDM are varied (Table II). The male excess in KPDM indicates that there may be other causes and mechanisms involved. In the limited discussion in the literature on the possible mechanisms underlying the excess susceptibility of males to KPDM, it has been suggested that the lifestyle and gender hormones in males may be responsible. It is our belief that it has been attributed to body fat distribution, hormonal factors, susceptibility to glucotoxicity and lipotoxicity, and changes in insulin sensitivity, which duality may result in a different and relatively severe deficiency of insulin action on glucose metabolism in KPDM.

Table II. Potential factors of diabetic ketosis in KPDM and possible mechanisms of male predominance.

Table II.

Potential factors of diabetic ketosis in KPDM and possible mechanisms of male predominance.

Triggers of diabetic ketosis in KPDM	Precipitate factors may lead to male predominance in KPDM
Infection	Difference in body fat distribution
Non-compliance with therapy such as omission of/or inadequate insulin therapy	Gender-related hormones including estrogen, testosterone, SHBG and other hormones (leptin and GH)
New onset diabetes	Lifestyle including smoking, alcohol abuse and heavy soft-drink consumption
Stress	Susceptibility to glucotoxicity and/or lipotoxicity
Surgery, heart attack and stroke	Virus infection (HHV-8 or Coxsaekie B)
Alcohol or drug abuse	X-linked G6PD deficiency
	Mutation Gly574Ser in the HNF1A gene, GCK, HNF, PDX-1, PAX-4 and NGN3

[i] SHBG, sex hormone-binding globin; GH, growth hormone; HHV-8, human herpes virus 8; GCK, glucokinase; HNF, hepatocyte nuclear factor; PDX-1, pancreatic and duodenal homeobox-1; PAX-4, paired box gene-4; NGN3, neurogenin3; G6PD, glucose-6-phosphate dehydrogenase; HNF1A, hepatocyte nuclear factor 1 homeobox A; KPDM, ketosis-prone diabetes mellitus.

Body fat distribution and insulin sensitivity

KPDM was more frequent in men compared to women and in obese compared to non-obese participants. Gender differences in KPDM may be associated with a different impact of obesity in men and women. An important gender difference in body fat distribution is generally observed, and consideration should be given between the genders. Gender differences in body composition and/or insulin sensitivity are evident in humans throughout the lifespan. Gender differences in body fat distribution are well-recognized, with men accumulating adipose tissue in the visceral area to a much greater extent than women. Accordingly, the amount of visceral adipose tissue fat is twice as high in men as in women (16). Otsuki et al (6) found that there were gender differences of age-dependent changes of insulin sensitivity, but not of insulin secretory activity, in Japanese non-diabetic subjects. This gender difference in body fat distribution and its associated insulin sensitivity has been shown to explain a major portion of the differing metabolic profiles and DKA risk in male and female diabetic patients.

Gender-related hormones and other hormones

There is strong evidence for gender differences in the incidence and presentation of the majority of disease processes (17), in addition to a long-standing knowledge that men and women differ in the most basic metabolic processes. There is a well-known sexual dimorphism in terms of androgen metabolism. Evidence showed that estrogen may have favorable effects on insulin sensitivity, whereas androgens may have undesirable effects on it. Androstenedione is known to be the precursor of testosterone and estrone. The elevated androstenedione levels during lipid/heparin infusion resulted in an increase of testosterone and dihydrotestosterone. However, a potential mechanism linking elevated free fatty acids/triglycerides and androgens was not presented in the study (19). Other hormones also influence insulin sensitivity, accounting for gender differences of the development of diabetic ketosis. For example, serum leptin concentrations have been demonstrated as higher in female mice compared to males. In addition, the effects of growth hormones on glucose, lipid and protein metabolism were also revealed recently (18). However, there are few population-based studies of gender differences in insulin sensitivity (20).

Glucolipotoxicity susceptibility and lifestyle

Increasing clinical data suggest that patients with KPDM are more susceptible to glucotoxicity or lipotoxicity, if not glucolipotoxicity, in obese male individual (21,22). As it is frequently associated with obesity and hyperlipidemia, as well as hyperglycemia, certain investigators have examined whether high levels of free fatty acids or other lipids may be the underlying trigger of unprovoked DKA or ketosis. Accumulating evidence shows that severe glucotoxic blunting of an intracellular pathway leading to insulin secretion may contribute to the reversible β-cell dysfunction characteristic of KPDM patients (22). Differences in the lifestyle of males, including active use of cocaine or alcohol abuse, may also have an impact on the incidence of diabetes and these findings call for further studies in this respect (23).

Susceptibility to potential virus infections

Is it possible that the KPDM in Chinese patients described by Tan et al (13) represents an attack by disease source factors, such as virus or bacteria. However, there was no adequate evidence that patients with KPDM had an infectious illness. It has been hypothesized that differences in susceptibility to infections may be associated with an X- or Y-linked histocompatibility locus. It has been shown that gender differences with male predominance occur in the incidence of mumps, Coxsaekie B virus, adenovirus, echovirus and polio virus infections in humans (24–27). Sobngwi et al (27) found a high association between KPDM and human herpes virus-8 infection and evidenced that this virus was able to infect human β-cells in vitro (25). The possibility of virus infections for the development of KPDM remains uncertain. Recent findings of male predominance do not allow any conclusions to be drawn concerning increased susceptibility to virus infections in males (26).

Genetic susceptibility

Recent evidence shows that genetic susceptibility contributes to KPDM. However, it remains unknown whether the model is polygenic or has a major gene influence. A point mutation, Gly574Ser, in the hepatocyte nuclear factor 1 homeobox A (HNF1A) gene was proposed as a marker of KPDM in African-American adolescents (28), but a recent study in adults excluded this association (29). Sonbgwi et al (30) investigated the possibility of X-linked glucose-6-phosphate dehydrogenase (G6PD) deficiency as a genetic basis for the male-predominant KPDM phenotype in West African populations. They found a higher prevalence of functional G6PD deficiency in the KPDM patients compared to patients with type 2 diabetes and an association between β-cell functional reserve and erythrocyte G6PD activity; however, the functional G6PD deficiency was not matched by a higher prevalence of G6PD gene mutations. Therefore, G6PD dysfunction may contribute to impaired β-cell defense against oxidant stress with regards to acute hyperglycemia, but its cause does not appear to be a genetic mutation. A previous study confirmed that the majority (70%) of the A-β- KPDM patients had no significant causal polymorphisms in either the proximal promoter or coding regions of 7 genes, including glucokinase, HNF1A and HNF1B, pancreatic and duodenal homeobox 1, β2/NeuroD1 and paired box gene 4. The investigators regarded that A-β- KPDM is more likely to not be a predominantly monogenic diabetic syndrome (31,32). The previous study by Louet et al (33) showed that neurogenin-3 variations may influence the pathogenesis of KPDM in West African populations but did not show an association with gender distribution. Taken together, these results suggest that upon further consideration and following future directions, these studies have the potential to inform us with regards to gender differences in the regulation of metabolic signals and how to proceed. Additional pathophysiology insight is required to provide an improved understanding of gender distribution with male predominance in KPDM.

Conclusion

In conclusion, KPDM is a complex and heterogeneous disease with environmental and genetic factors influencing pathophysiology and clinical progression significantly (32). Currently, the syndromes of KPDM and its specific complications appear to be increasingly recognized worldwide. However, gender differences between men and women with DKA and the mechanisms of the male predominance in KPDM are too complicated and often subtle. Proper clinical epidemiological surveys remain to be conducted. Increasing information provides insights into possible differences in pathogenesis, and intervention strategies of KPDM. Gender differences in KPDM could provide important information for the pathogenesis of DKA. The male predominance in KPDM may have therapeutic indications for potential tailored pharmacological intervention in diabetes and its associated complications. Further research on this subject should be conducted.

References