Phenotypes of Patients with Diabetes and NAFLD: Comparison
View Latest Version
Please note this is a comparison between Version 2 by Sirius Huang and Version 1 by Andreea Ciudin Mihai.

Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease in Western countries. Its incidence is expected to keep growing, parallel to the incidence of metabolic syndrome (MetS) and its determinants. Within the MetS spectrum, the bulk of research addresses the relationship between either type 2 diabetes (T2DM) or obesity with NAFLD. However, a growing body of evidence shows that NAFLD is also prevalent in a variety of other forms of diabetes that typically have an earlier onset, such as type 1 diabetes (T1DM), Maturity-onset Diabetes of the Young (MODY) and ketosis-prone diabetes. 

  • type 2 diabetes
  • type 1 diabetes
  • ketone-prone diabetes
  • MODY diabetes
  • NAFLD

1. Type 2 Diabetes and Obesity—The Metabolic Syndrome Paradigm

1.1. Epidemiology

Type 2 diabetes is the most common form of diabetes. It has an estimated prevalence of 26.9 million people of all ages in the US (or 8.2% of the US population) and 536.6 million people worldwide [11,12][1][2]. In Spain, the incidence of DM obtained from the di@bet.es study cohort was estimated at 11.6 cases/1000 person-year (OR (95% CI) 11.1–12.1) [13][3]. T2DM is characterized by hyperglycemia, IR, and relative insulin deficiency [14][4]. The primary risk factors associated are those related to lifestyle behaviors such as poor physical inactivity and dietary habits, cigarette smoking, and alcohol consumption [15][5]. Moreover, overweightness and obesity contribute to approximately 89% of cases of T2DM [11][1].
T2DM has become an epidemic issue in occidental countries. Due to its asymptomatic onset, it is frequently diagnosed at later stages when micro and macrovascular complications are established [16][6]. Optimization of management of T2DM, screening in primary care, and advances in research have allowed a decrease in the associated complications [17][7]. In addition, obesity is directly linked to NAFLD due to IR and metabolic syndrome [18,19][8][9].
The 2020 Center for Disease Control and Prevention (CDC) report revealed 34.1 million patients diagnosed with diabetes among adults aged 18 years or older in the United States, with type 2 diabetes accounting for 90% to 95% of cases. Among the reported cases, 45.8% of individuals had obesity (body mass index (BMI) of 30.0 to 39.9 kg/m2), and 15.5% presented extreme obesity (BMI of 40.0 kg/m2 or higher) [11][1].
In global studies, the prevalence of T2DM is estimated at 10.5% [12][2], which has steadily increased during the last two decades due to changes in nutrition and physical exercise in Western countries. According to current predictions, the incidence of T2DM is expected to rise from 171 million in 2000 to 366 million individuals by 2030 [20][10]. One of the main drivers of such worrying forecasting is the increased prevalence of childhood obesity, with approximately 35.1% and 26.5% of children being overweight or obese in the US, respectively [21][11]. Social determinants of health such as gender, race/ethnicity, and socio-economic status expose significant disparities amongst T2DM patients. For example, Black and Hispanic children have higher risk-adjusted obesity odds when compared to Asians or Caucasians [22][12]. Similar results are described for T2DM, with the highest prevalence among people of Hispanic origin (12.5%) and Blacks (11.7%) [11][1]. Low socioeconomic status has been found also associated with poorer outcomes [23][13]. Lifestyle behaviors, e.g., physical inactivity, smoking, or alcohol consumption, are also strong drivers of T2DM, independently of genetic predisposition [15,24][5][14].

1.2. Pathophysiology

Type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD) have been traditionally linked to one another. The main pathophysiological link between T2DM and NAFLD is IR [25][15], and hepatic steatosis and fibrosis are also related to the development of IR, which substantially increases the risk of subsequent T2DM [3][16]. On one hand, hyperglycemia was demonstrated to be a hazard in hepatic steatosis and fibrosis development: several in vitro models demonstrate the role of hyperglycemia in the process, e.g., Robin C et al. in 2017, demonstrated that hyperglycemic cell culturing conditions induced steatosis within a human hepatocyte cell line (HepG2 cells) by the accumulation of intracellular lipids [26][17]. Experimental models, such as in streptozotocin-induced diabetic models in mice, show that progression in NAFLD is due to hyperglycemia-induced inflammation [27][18]. An increase in glucose substrate in the hepatocyte promotes the accumulation of free fatty acids in the cell and the stimulation of hepatic lipogenesis by upregulation of the Krebs cycle and an increase in the expression of ChREBPnad liver X receptor alfa. This cascade activates downstream fibrogenic pathways with oxidant stress and inflammasome activation that leads to cell apoptosis by cytokines such as IL-1B, IL-6, or TNF-alfa that finally result in inflammation, hepatocyte injury, and liver fibrosis [28,29,30][19][20][21]. On the other hand, the excess of triglyceride synthesis is another pathophysiological landmark of NAFLD. IR was proven to be responsible for an increase in adiposity in hepatic cells, as demonstrated in studies with the hyperinsulinemic-euglycemic clamp [31][22] and indirectly measured through the HOMA-IR index [32][23]. These changes result in a boost of gluconeogenesis cascades, an increase in free fatty acid (FFA) levels, and simultaneously impairment in hepatic glycogen synthesis. These metabolic changes lead to liver fat accumulation, resulting in a preferential shift from carbohydrate to FFA beta-oxidation [33][24]. FFA accumulation and IR activate several inflammatory pathways related to pro-inflammatory cytokines such as TNFα or IL-6 [34][25]. Other extrahepatic drivers of liver inflammation include IL-1B, or IL-6 liberated from adipose tissue in obese individuals [35][26]. These cytokines create a pro-inflammatory environment producing hepatotoxic free oxygen radical species that result in hepatocellular injury and fibrosis [36][27].
Despite of that, not all patients with NASH exhibit IR. This suggests that other factors may influence the progression to NASH. For example, genetic variants are strongly associated with histologic severity. Petersen et al. demonstrated that specific polymorphisms in the gene encoding for apolipoprotein C3 are markers of hepatic IR and inflammation [37][28], such as other research related IL-6 polymorphisms [38][29]. Patatin-like phospholipase domain-containing protein 3 (PNPLA3) is a lipid droplet-associated protein that is increased in obese patients. Higher levels are associated with augmented liver fat content [39][30]. Finally, hepatic lipid metabolism disruptions, inflammation in adipose tissue, and ectopic sites of fat deposition interfere with normal hepatic function and give way to excess storage of lipid droplets in hepatocytes [40][31]. In fact, de novo lipogenesis is threefold higher in patients with NAFLD [41][32]. In addition, hepatocellular FFA accumulation is sustained by impaired synthesis and secretion of very-low-density lipoproteins and excessive importation of FFA from adipose tissue [42][33]. The activation of these cascades eventually leads to impaired antioxidant capacity with increased oxidative stress and mitochondrial function defects, leading to hepatic fibrosis and IR [36][27].

1.3. Clinical Manifestations

T2DM and obesity are among the most important risk factors of NASH, liver-related events, hepatocellular carcinoma (HCC), and mortality in patients with NAFLD [43,44,45,46][34][35][36][37]. The prevalence of NAFLD in T2DM patients is over 50%, and when both T2DM and obesity coexist, the prevalence of NAFLD ranges between 60% and 80% [47,48,49,50][38][39][40][41]. A global meta-analysis showed that T2DM was present in 22.51% of patients with radiologically defined NAFLD and 43.36% among patients with NASH determined by biopsy. Of note, 56% of the individuals with histologically proven NASH had normal liver enzymes [2,43][34][42]. Data recollected from the Edinburgh Type 2 Diabetes Study (ET2DS) registered a prevalence of 42.6% of NAFLD in patients with T2DM. Independent predictors were BMI, duration of diabetes, HbA1c, triglycerides, and metformin use [51][43]. These studies also showed that some factors play a critical role in the relationship between NAFLD and diabetes. For example, compared to T2DM only, patients with T2DM and NAFLD were more likely to present hypertension, dyslipidemia, and cardiovascular diseases [52][44] which means that the presence of NAFLD determines a higher risk of poor cardiovascular and metabolic outcomes, a fact that was proven in previous studies. Indeed, a meta-analysis including 16 studies representing more than 34,000 patients demonstrated that NAFLD was associated with a higher cardiovascular risk and conferred a more elevated risk adjusted-odds of cardiovascular events, including myocardial infarction and stroke [53][45].
Emerging data suggest that up to 20% of patients diagnosed with NASH will develop cirrhosis in the disease course [54][46]. The fibrosis stage is the main predictor of liver-related illness, liver transplantation, and liver-related mortality [2,43][34][42]. Both T2DM and overweight/obesity are predictors of advanced fibrosis and comorbidities in patients with NASH [45,55][36][47] with a >10-fold risk of HCC [56][48]. Remarkably, and contrary to other causes of chronic liver disease, HCC can develop in non-cirrhotic livers in the setting of NAFLD. In addition, patients with obesity have an increased incidence of HCC without cirrhosis compared with non-obese patients [57,58][49][50]. Numerous studies linked pro-inflammatory cytokines derived from IR and hyperinsulinemia to activation of carcinogenic pathways [59][51]. Yet, cardiovascular events such as stroke or myocardial infarction are the leading cause of death in patients with NAFLD [60][52]. NAFLD also is shown to worsen the prognosis of T2DM, e.g., to worsen glycemic control and microvascular complications such as nephropathy and retinopathy [61,62][53][54]. To remark, another factor with a close relationship with metabolic syndrome is the presence of hepatitis virus C infection (HCV). Recent evidence from prospective studies suggests that the treatment of HCV in NAFLD patients with and without fibrosis, would reduce the risk of T2DM by 81% by restoring normal glucose metabolism. The same effect was reported for cardiovascular events such as acute coronary syndrome, myocardial infarction, stroke, or transient ischemic attack, with a decrease between 56 and 75 cases per year for 10,000 HCV patients with long-term remission, independently of other risk factors such as smoking, dyslipidemia, or hypertension [63,64,65][55][56][57].

2. Type 1 Diabetes (T1DM)

Although it appears that the most common liver disease in patients with T1DM is NAFLD [98][58], the links between both disorders remain largely unelucidated. T1DM is an autoimmune disorder that typically presents in children and younger adults. Until recently, there was not a traditional association between obesity, metabolic syndrome, and T1DM [14][4], yet with the increasing prevalence of obesity in the general population, a parallel rise has been observed in patients with T1DM and overweight or obesity [99][59]. Moreover, a pathogenic role of obesity in T1DM was recently described, related to β-cell stress, ectopic adipose tissue, and an increase in autoimmune disorders [100,101,102][60][61][62].

2.1. Epidemiology

A global increase in T1DM incidence has been observed, with a 2–3% increase per year [103,104,105][63][64][65]. The higher incidence is found among children younger than five years, and variations occur according to environmental and behavioral factors such as diet, obesity, vitamin D sufficiency, gut-microbiome changes, or exposure to certain viruses [100,105][60][65]. As in the case of T2DM, socioeconomic factors play a paramount role in the differences in the prevalence among genetically similar patients [106][66]. Although T1DM can also develop in adulthood, the higher incidence of T2DM among adults and the lack of strong diagnostic criteria make such late diagnosis rare and challenging [107][67].

2.2. Pathophysiology

Although T1DM and T2DM share hyperglycemia as their landmark, various underlying mechanisms primarily differentiate both entities. While an absolute insulin deficiency characterizes T1DM, the natural history of T2DM is marked by IR in peripheral tissues. Yet, T2DM can also lead to insulin deficiency when insulin production is depleted due to exhaustion of pancreatic synthesis [14,108][4][68]. As in T2DM, the state of hyperinsulinemia found in T1DM affects glucose and lipid liver metabolism and triggers pro-inflammatory cascades that produce liver fibrosis and cirrhosis [3,29,109,110][16][20][69][70].
A proposed differential mechanism of liver damage in T1DM relates to the increase in visceral adiposity secondary to frequent snacking in the hypoglycemia context, which increases caloric and fructose intake [111][71]. Other mechanisms that may explain the development of hepatic complications in patients with T1DM are the relative portal vein insulin deficiency that leads to altered hepatic glycogen storage, absence of inhibition of hepatic gluconeogenesis, and overall metabolic disturbance with a shunt to lipogenic pathways [14,112,113][4][72][73]. The lack of endogenous insulin also alters the dynamic of insulin delivery with more minor variation in the plasma range, ending in downregulation of insulin receptors on hepatic cells due to continuous exposure [114][74]. This altered pharmacokinetics implies the development of a relative IR with the subsequent hepatic damage [109][69].
As mentioned above, not all patients with NAFLD are associated with obesity and MetS. This statement acquires relevance in T1DM due to its genetic footprint. Several genetic risk alleles associated with fatty liver disease are described in the literature, including those containing the genes PNPLA3 and transmembrane six superfamily member 2 (TM6SF2) [115][75]. Other potential genes that are related to T1DM and insulin-dependent T2DM are those that encode sterol regulatory element-binding protein (SREBPs) and carbohydrate-responsive element-binding protein (ChREBP). Alterations in these proteins stimulate lipogenic and glycolytic pathways that contribute to NAFLD [116,117][76][77].

2.3. Clinical Manifestations

Despite T1DM being at an increased risk of developing NAFLD, likely higher than T2DM patients (both because of the intensity of metabolic dysfunction and the earlier onset of the disease), a limited number of studies are addressing the prevalence of NAFLD in T1DM. A meta-analysis by Vries et al. reported an overall prevalence of 19.3% in T1DM, which increased to 22% in adults [98][58]. A recent study showed a NAFLD prevalence of 16–21% in T1DM patients by share wave elastography at liver ultrasound [118][78].
Evidence on the outcomes of patients with NAFLD and T1DM is also preliminary. In a cohort of 4641 patients with T1DM, Harman et al. found that overall, patients with T1DM were at increased risk of developing liver cirrhosis compared to the general population [119][79]. Targher et al. demonstrated that NAFLD increases the risk of both microvascular and macrovascular complications in T1DM, i.e., chronic kidney disease (37.8% vs. 9.9% in patients without NAFLD), retinopathy (53.2% vs. 19.8%), coronary artery disease (10.8% vs. 1.1%), cerebrovascular (37.3% vs. 5.5%), and peripheral vascular disease (24.5% vs. 2.5%, p < 0.001 for all comparisons) [53,120][45][80]. Further prospective studies are needed to evaluate whether NAFLD is an independent factor for hepatic and cardiometabolic complications that might contribute to the excess mortality in T1DM cohorts [121,122][81][82].

3. MODY Diabetes

MODY is a mild, largely asymptomatic form of diabetes that occurs in nonobese children and young adults with a dominant inheritance pattern [140][83]. This form of diabetes is commonly misdiagnosed as T1DM or T2DM and is often inappropriately managed with insulin, whereas the adequate treatment consists of a sulfonylurea [141,142][84][85].

3.1. Epidemiology

MODY represents a clinically heterogeneous form of β-cell dysfunction caused by genetic mutations with an autosomal dominant form of inheritance. Because of the diverse patterns of presentation and the need for costly molecular diagnosis, it is frequently misdiagnosed as other types of diabetes [142,143][85][86]. HNF-1α/MODY3 and GCK/MODY 2 are the most common mutations [144,145][87][88]. One of the first prevalence studies estimated 35.2 cases per million with a confirmed genetic test in the UK [146][89]. In a study carried out on Norwegian diabetes registers, MODY accounted for 0.4% of patients [147][90]. In the US, the estimated prevalence is 2.1 per 100,000 individuals younger than 20 years [148][91]. In these groups, researchers include a subtype of inherited diabetes associated with lipodystrophies that are associated with severe insulin resistance, premature diabetes, hypertriglyceridemia, and hepatic steatosis due to defects on adipocyte development, differentiation, and apoptosis [149,150][92][93]. Although acquired lipodystrophies related with chronic corticosteroids therapy or human immunodeficiency virus (HIV) infection are more common in the general population [151][94], this group is characterized by a translocation of subcutaneous adipose to ectopic parts of the body, including the liver, which subsequently drives to hepatic inflammation and fibrosis. Therefore, NAFLD has been described in these patients, as confirmed in histologically confirmed cohorts, with a prevalence around 82–90% [152,153,154][95][96][97]. Clinicians must be aware that some of these patients are characterized by low weight and BMI; therefore, recent guidelines recommend the screening of lipodystrophy in lean individuals with a diagnosis of NASH [155][98]. The severity of NAFLD will depend on the type of lipodystrophy, being more severe in generalized lipodystrophy, but also on specific mutations, such as LMNA mutations [156][99].

3.2. Pathophysiology

MODY was recognized as a disease in 1964 at the Fifth Congress of the International Diabetes Federation in Toronto, and since then, significant progress has been made in understanding its pathophysiology [157][100]. In 1974, Tattersall et al. reported a new form of diabetes with an autosomal dominant pattern of inheritance that typically presented in young patients who could discontinue insulin therapy over the course of the disease [158][101]. Since 1975, various mutated genes were identified and associated with different subtypes of MODY with a wide diversity of clinical features, severity of hyperglycemia, and age onset [159][102]. GCK (MODY 2) and HNF1A (MODY 3) mutations account for almost 70% of all cases of MODY, followed by HNF4A (MODY 1). HNF1A and HNF4A genes encode the transcription factors hepatocyte nuclear factor-1 alpha and factor-4 alpha [160][103] and coordinate gene expression of proteins involved in glucose transport and glucose metabolism, and β-cell apoptosis, which lead to an increase in cellular apoptosis and defects in insulin secretion [161][104]. The Glucokinase gene is responsible for detecting bloodstream glucose by its transformation to glucose-6-phosphate by the glucose transporter 2 (GLUT2). Heterozygous mutations imply less function of this enzyme, and affected β-cells are less sensitive to glucose variations that result in elevated fasting and postprandial blood sugar.

3.3. Clinical Manifestations

Patients diagnosed with the most common forms (MODY 1, 2, and 3) have a similar risk for complications as those with T1DM and T2DM. Therefore, an optimal glycemic control is inversely related to poor micro- and macrovascular outcomes [161][104]. Patients carrying heterozygous mutations rarely develop micro- or macrovascular complications [162][105]. Concerning the association of MODY and NAFLD, again, the body of evidence is overall poor. Multisystemic forms that imply alterations in the transcription factor hepatocyte nuclear factor 1β (HNF1B) (MODY 5) with clinical features that include early-onset diabetes mellitus, pancreatic hypoplasia, genital tract, kidney hypoplasia, cognitive impairment, and abnormal liver function might be the subgroup at higher risk of NAFLD. Hepatic dysfunction is presented in 65% of patients, and the classical phenotype is characterized by elevated serum transaminases, steatosis, and periportal fibrosis. Yearly abdominal ultrasonography and biannual laboratory monitoring are proposed for patients with MODY 5 [163,164,165][106][107][108].

4. Ketone-Prone Diabetes (KPD)

In 1987, Winter et al. reported a new form of diabetes called ‘atypical diabetes’ by then [171][109]. The discovery led to a rise in recognizing this uncommon clinical presentation, with an abrupt onset—typically with ketoacidosis—and transient insulin requirements that usually occurred in African-American or Hispanic patients and were associated with obesity and a strong family history of type 2 diabetes [172,173,174,175][110][111][112][113]. Some evidence suggests that a primary glucose desensitization acts as a trigger to β-cell exhaustion and dysfunction that lead to acute metabolic failure. Initial aggressive treatment with insulin therapy and antidiabetic drugs such as metformin predict better outcomes and a delay in the recurrence of hyperglycemia [176,177][114][115].

4.1. Epidemiology

These patients are often Afro-American and Hispanic, obese, middle-aged men, with a family history of type 2 diabetes. Most prevalence studies on KPD made are US-based, with an estimate of 20% and 50%, respectively, in African American and Hispanic patients with new diagnoses of diabetic ketoacidosis [171,173,178,179][109][111][116][117]. Obesity is present in 56% of newly diagnosed patients, and more than 80% of patients have a family history of T2DM [180,181][118][119]. More recent studies estimated an average incidence of 60% among patients attending emergency rooms due to ketoacidosis [182][120]. The prevalence of this diabetes seems to be lower in Asian and White Americans, representing less than 10% of cases of diabetic ketoacidosis [183,184][121][122]. Patients with KPD present with acute IR, elevated glucose, Hb1Ac, and ketone levels, and unlike T1DM, they do not exhibit β-cell antibodies.

4.2. Pathophysiology

The natural history of KPD has two phases. These individuals initially present an acute form presentation with severe hyperglycemia and ketosis due to a lack of response and stimulus of β-cell insulin secretion [178][116]. The causes of these acute onsets in patients affected with ketosis-prone diabetes remain unknown. Patients present a diminished insulin and c-peptide response to an oral glucose load in the second phase. In studies with a euglycemic insulin clamp, there was no difference in baseline glucagon levels and glucagon suppression between KPD patients and the normal controls. In short term follow-up, the insulin secretion increased after a few weeks of exogenous insulin treatment, and after months, there was no difference in the beta-cell response and the insulin secretion compared to controls [185][123]. IR is not systematically found and appears to be associated with ethnicity and geographic variability [186,187][124][125].

4.3. Clinical Manifestations

The typical presentation is a new clinical onset with severe hyperglycemia with high ketones or diabetic ketoacidosis, negative GAD, and islet cell autoantibodies. The type and rate of complications are similar to T2DM [162,164,165,166][105][107][108][126]. Provided that IR characterizes KPD and related metabolic abnormalities, pathogenic liver pathways that contribute to NAFLD are certainly stimulated; yet, there are no specific studies of NAFLD in KPD. It is worth underscoring that African Americans with T2DM are at lower risk for hepatic steatosis than White Americans, which is not explained by ethnic differences in BMI, HOMA-IR, or toxic or drug ingestion [55,180][47][118]. In contrast, Hispanics are at higher risk of steatohepatitis, seemingly due to the higher prevalence of obesity and IR [188,189][127][128].

References

  1. Centers for Disease Control and Prevention. National Diabetes Statistics Report Website. Available online: https://www.cdc.gov/diabetes/data/statistics-report/index.html (accessed on 20 March 2022).
  2. Sun, H.; Saeedi, P.; Karuranga, S.; Pinkepank, M.; Ogurtsova, K.; Duncan, B.B.; Stein, C.; Basit, A.; Chan, J.C.; Mbanya, J.C.; et al. IDF Diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Res. Clin. Pract. 2021, 183, 109119.
  3. Rojo-Martínez, G.; Valdés, S.; Soriguer, F.; Vendrell, J.; Urrutia, I.; Pérez, V.; Ortega, E.; Ocón, P.; Montanya, E.; Menéndez, E.; et al. Incidence of diabetes mellitus in Spain as results of the nation-wide cohort study. Sci. Rep. 2020, 10, 2765.
  4. Melmed, S.; Williams, R.H. Williams Textbook of Endocrinology, 14th ed.; Elsevier/Saunders: Philadelphia, PA, USA, 2014.
  5. Fletcher, B.; Gulanick, M.; Lamendola, C. Risk Factors for Type 2 Diabetes Mellitus. J. Cardiovasc. Nurs. 2002, 16, 17–23.
  6. Faselis, C.; Katsimardou, A.; Imprialos, K.; Deligkaris, P.; Kallistratos, M.S.; Dimitriadis, K. Microvascular Complications of Type 2 Diabetes Mellitus. Curr. Vasc. Pharmacol. 2020, 18, 117–124.
  7. Zheng, Y.; Ley, S.H.; Hu, F.B. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat. Rev. Endocrinol. 2018, 14, 88–98.
  8. Cholongitas, E.; Pavlopoulou, I.; Papatheodoridi, M.; Markakis, G.E.; Bouras, E.; Haidich, A.; Papatheodoridis, G. Epidemiology of nonalcoholic fatty liver disease in Europe: A systematic review and meta-analysis. Ann. Gastroenterol. 2021, 34, 404–414.
  9. Marchesini, G.; Brizi, M.; Bianchi, G.; Tomassetti, S.; Bugianesi, E.; Lenzi, M.; McCullough, A.J.; Natale, S.; Forlani, G.; Melchionda, N. Nonalcoholic Fatty Liver Disease: A Feature of the Metabolic Syndrome. Diabetes 2001, 50, 1844–1850.
  10. Wild, S.; Roglic, G.; Green, A.; Sicree, R.; King, H. Global Prevalence of Diabetes. Diabetes Care 2004, 27, 1047–1053.
  11. Skinner, A.C.; Ravanbakht, S.N.; Skelton, J.A.; Perrin, E.M.; Armstrong, S.C. Prevalence of Obesity and Severe Obesity in US Children, 1999–2016. Pediatrics 2018, 141, e20173459.
  12. Sa, J.; Cho, B.-Y.; Chaput, J.-P.; Chung, J.; Choe, S.; Gazmararian, J.A.; Shin, J.C.; Lee, C.G.; Navarrette, G.; Han, T. Sex and racial/ethnic differences in the prevalence of overweight and obesity among U.S. college students, 2011–2015. J. Am. Coll. Health 2019, 69, 413–421.
  13. Bijlsma-Rutte, A.; Rutters, F.; Elders, P.J.; Bot, S.D.; Nijpels, G. Socio-economic status and HbA1c in type 2 diabetes: A systematic review and meta-analysis. Diabetes/Metabolism Res. Rev. 2018, 34, e3008.
  14. Canedo, J.R.; Miller, S.T.; Schlundt, D.; Fadden, M.K.; Sanderson, M. Racial/Ethnic Disparities in Diabetes Quality of Care: The Role of Healthcare Access and Socioeconomic Status. J. Racial Ethn. Health Disparities 2017, 5, 7–14.
  15. Stepanova, M.; Rafiq, N.; Younossi, Z.M. Components of metabolic syndrome are independent predictors of mortality in patients with chronic liver disease: A population-based study. Gut 2010, 59, 1410–1415.
  16. Marchesini, G.; Brizi, M.; Morselli/labate, A.M.; Bianchi, G.; Bugianesi, E.; McCullough, A.J.; Forlani, G.; Melchionda, N. Association of nonalcoholic fatty liver disease with insulin resistance. Am. J. Med. 1999, 107, 450–455.
  17. Su, R.C.; Lad, A.; Breidenbach, J.D.; Blomquist, T.M.; Gunning, W.T.; Dube, P.; Kleinhenz, A.L.; Malhotra, D.; Haller, S.T.; Kennedy, D.J. Hyperglycemia induces key genetic and phenotypic changes in human liver epithelial HepG2 cells which parallel the Leprdb/J mouse model of non-alcoholic fatty liver disease (NAFLD). PLoS ONE 2019, 14, e0225604.
  18. Harada, S.; Miyagi, K.; Obata, T.; Morimoto, Y.; Nakamoto, K.; Kim, K.I.; Kim, S.K.; Kim, S.R.; Tokuyama, S. Influence of hyperglycemia on liver inflammatory conditions in the early phase of non-alcoholic fatty liver disease in mice. J. Pharm. Pharmacol. 2017, 69, 698–705.
  19. Samuel, V.T.; Shulman, G.I. Nonalcoholic Fatty Liver Disease as a Nexus of Metabolic and Hepatic Diseases. Cell Metab. 2018, 27, 22–41.
  20. Friedman, S.L.; Neuschwander-Tetri, B.A.; Rinella, M.; Sanyal, A.J. Mechanisms of NAFLD development and therapeutic strategies. Nat. Med. 2018, 24, 908–922.
  21. Abdul-Wahed, A.; Guilmeau, S.; Postic, C. Sweet Sixteenth for ChREBP: Established Roles and Future Goals. Cell Metab. 2017, 26, 324–341.
  22. Labadzhyan, A.; Cui, J.; Péterfy, M.; Guo, X.; Chen, Y.-D.I.; Hsueh, W.A.; Rotter, J.I.; Goodarzi, M.O. Insulin Clearance Is Associated with Hepatic Lipase Activity and Lipid and Adiposity Traits in Mexican Americans. PLoS ONE 2016, 11, e0166263.
  23. Singh, A.S.B. Surrogate markers of insulin resistance: A review. World J. Diabetes 2010, 1, 36–47.
  24. Krssak, M.; Brehm, A.; Bernroider, E.; Anderwald, C.; Nowotny, P.; Man, C.D.; Cobelli, C.; Cline, G.W.; Shulman, G.I.; Waldhaäusl, W.; et al. Alterations in Postprandial Hepatic Glycogen Metabolism in Type 2 Diabetes. Diabetes 2004, 53, 3048–3056.
  25. Tilg, H.; Diehl, A.M. Cytokines in Alcoholic and Nonalcoholic Steatohepatitis. N. Engl. J. Med. 2000, 343, 1467–1476.
  26. Moschen, A.; Molnar, C.; Geiger, S.; Graziadei, I.; Ebenbichler, C.; Weiss, H.; Kaser, S.; Kaser, A.; Tilg, H. Anti-inflammatory effects of excessive weight loss: Potent suppression of adipose interleukin 6 and tumour necrosis factor expression. Gut 2010, 59, 1259–1264.
  27. Sanyal, A.J.; Campbell–Sargent, C.; Mirshahi, F.; Rizzo, W.B.; Contos, M.J.; Sterling, R.K.; Luketic, V.A.; Shiffman, M.L.; Clore, J.N. Nonalcoholic steatohepatitis: Association of insulin resistance and mitochondrial abnormalities. Gastroenterology 2001, 120, 1183–1192.
  28. Petersen, K.F.; Dufour, S.; Hariri, A.; Nelson-Williams, C.; Foo, J.N.; Zhang, X.-M.; Dziura, J.; Lifton, R.P.; Shulman, G.I. Apolipoprotein C3 Gene Variants in Nonalcoholic Fatty Liver Disease. N. Engl. J. Med. 2010, 362, 1082–1089.
  29. Carulli, L.; Canedi, I.; Rondinella, S.; Lombardini, S.; Ganazzi, D.; Fargion, S.; De Palma, M.; Lonardo, A.; Ricchi, M.; Bertolotti, M.; et al. Genetic polymorphisms in non-alcoholic fatty liver disease: Interleukin-6−174G/C polymorphism is associated with non-alcoholic steatohepatitis. Dig. Liver Dis. Off. J. Ital. Soc. Gastroenterol. Ital. Assoc. Study Liver 2009, 41, 823–828.
  30. Hotta, K.; Yoneda, M.; Hyogo, H.; Ochi, H.; Mizusawa, S.; Ueno, T.; Chayama, K.; Nakajima, A.; Nakao, K.; Sekine, A. Association of the rs738409 polymorphism in PNPLA3 with liver damage and the development of nonalcoholic fatty liver disease. BMC Med. Genet. 2010, 11, 172.
  31. Donnelly, K.L.; Smith, C.I.; Schwarzenberg, S.J.; Jessurun, J.; Boldt, M.D.; Parks, E.J. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J. Clin. Investig. 2005, 115, 1343–1351.
  32. Lambert, J.E.; Ramos-Roman, M.A.; Browning, J.D.; Parks, E.J. Increased De Novo Lipogenesis Is a Distinct Characteristic of Individuals with Nonalcoholic Fatty Liver Disease. Gastroenterology 2014, 146, 726–735.
  33. Heeren, J.; Scheja, L. Metabolic-associated fatty liver disease and lipoprotein metabolism. Mol. Metab. 2021, 50, 101238.
  34. Angulo, P.; Kleiner, D.E.; Dam-Larsen, S.; Adams, L.A.; Björnsson, E.S.; Charatcharoenwitthaya, P.; Mills, P.R.; Keach, J.C.; Lafferty, H.D.; Stahler, A.; et al. Liver Fibrosis, but No Other Histologic Features, Is Associated with Long-term Outcomes of Patients with Nonalcoholic Fatty Liver Disease. Gastroenterology 2015, 149, 389–397.e10.
  35. Ekstedt, M.; Hagström, H.; Nasr, P.; Fredrikson, M.; Stål, P.; Kechagias, S.; Hultcrantz, R. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology 2015, 61, 1547–1554.
  36. Hossain, N.; Afendy, A.; Stepanova, M.; Nader, F.; Srishord, M.; Rafiq, N.; Goodman, Z.; Younossi, Z. Independent Predictors of Fibrosis in Patients with Nonalcoholic Fatty Liver Disease. Clin. Gastroenterol. Hepatol. 2009, 7, 1224–1229.
  37. Fracanzani, A.L.; Valenti, L.; Bugianesi, E.; Andreoletti, M.; Colli, A.; Vanni, E.; Bertelli, C.; Fatta, E.; Bignamini, D.; Marchesini, G.; et al. Risk of severe liver disease in nonalcoholic fatty liver disease with normal aminotransferase levels: A role for insulin resistance and diabetes. Hepatology 2008, 48, 792–798.
  38. Atan, N.A.D.; Koushki, M.; Motedayen, M.; Dousti, M.; Sayehmiri, F.; Vafaee, R.; Norouzinia, M.; Gholami, R. Type 2 diabetes mellitus and non-alcoholic fatty liver disease: A systematic review and meta-analysis. Gastroenterol. Hepatol. Bed Bench 2017, 10 (Suppl. 1), S1–S7.
  39. Oberaigner, W.; Ebenbichler, C.; Oberaigner, K.; Juchum, M.; Schönherr, H.R.; Lechleitner, M. Increased cancer incidence risk in type 2 diabetes mellitus: Results from a cohort study in Tyrol/Austria. BMC Public Health 2014, 14, 1058.
  40. Marengo, A.; Rosso, C.; Bugianesi, E. Liver Cancer: Connections with Obesity, Fatty Liver, and Cirrhosis. Annu. Rev. Med. 2016, 67, 103–117.
  41. Armandi, A.; Bugianesi, E.; Valenti, L. Natural history of NASH. Liver Int. 2021, 41 (Suppl. 1), 78–82.
  42. Sanyal, A.J.; Van Natta, M.L.; Clark, J.; Neuschwander-Tetri, B.A.; Diehl, A.; Dasarathy, S.; Loomba, R.; Chalasani, N.; Kowdley, K.; Hameed, B.; et al. Prospective Study of Outcomes in Adults with Nonalcoholic Fatty Liver Disease. N. Engl. J. Med. 2021, 385, 1559–1569.
  43. Williamson, R.M.; Price, J.F.; Glancy, S.; Perry, E.; Nee, L.D.; Hayes, P.C.; Frier, B.M.; Van Look, L.A.; Johnston, G.I.; Reynolds, R.M.; et al. Prevalence of and Risk Factors for Hepatic Steatosis and Nonalcoholic Fatty Liver Disease in People with Type 2 Diabetes: The Edinburgh Type 2 Diabetes Study. Diabetes Care 2011, 34, 1139–1144.
  44. Targher, G.; Bertolini, L.; Padovani, R.; Rodella, S.; Tessari, R.; Zenari, L.; Day, C.; Arcaro, G. Prevalence of Nonalcoholic Fatty Liver Disease and Its Association with Cardiovascular Disease among Type 2 Diabetic Patients. Diabetes Care 2007, 30, 1212–1218.
  45. Targher, G.; Bertolini, L.; Padovani, R.; Rodella, S.; Zoppini, G.; Pichiri, I.; Sorgato, C.; Zenari, L.; Bonora, E. Prevalence of non-alcoholic fatty liver disease and its association with cardiovascular disease in patients with type 1 diabetes. J. Hepatol. 2010, 53, 713–718.
  46. Matteoni, C.A.; Younossi, Z.M.; Gramlich, T.; Boparai, N.; Liu∥, Y.C.; McCullough, A.J. Nonalcoholic fatty liver disease: A spectrum of clinical and pathological severity. Gastroenterology 1999, 116, 1413–1419.
  47. Petta, S.; Amato, M.C.; Di Marco, V.; Cammà, C.; Pizzolanti, G.; Barcellona, M.R.; Cabibi, D.; Galluzzo, A.; Sinagra, D.; Giordano, C.; et al. Visceral adiposity index is associated with significant fibrosis in patients with non-alcoholic fatty liver disease. Aliment. Pharmacol. Ther. 2011, 35, 238–247.
  48. Dyson, J.; Jaques, B.; Chattopadyhay, D.; Lochan, R.; Graham, J.; Das, D.; Aslam, T.; Patanwala, I.; Gaggar, S.; Cole, M.; et al. Hepatocellular cancer: The impact of obesity, type 2 diabetes and a multidisciplinary team. J. Hepatol. 2013, 60, 110–117.
  49. Yasui, K.; Hashimoto, E.; Komorizono, Y.; Koike, K.; Arii, S.; Imai, Y.; Shima, T.; Kanbara, Y.; Saibara, T.; Mori, T.; et al. Characteristics of Patients with Nonalcoholic Steatohepatitis Who Develop Hepatocellular Carcinoma. Clin. Gastroenterol. Hepatol. 2011, 9, 428–433.
  50. Welzel, T.M.; Graubard, B.; Quraishi, S.; Zeuzem, S.; Davila, J.; El-Serag, H.B.; McGlynn, K. Population-Attributable Fractions of Risk Factors for Hepatocellular Carcinoma in the United States. Am. J. Gastroenterol. 2013, 108, 1314–1321.
  51. Aleksandrova, K.; Boeing, H.; Nöthlings, U.; Jenab, M.; Fedirko, V.; Kaaks, R.; Lukanova, A.; Trichopoulou, A.; Trichopoulos, D.; Boffetta, P.; et al. Inflammatory and metabolic biomarkers and risk of liver and biliary tract cancer. Hepatology 2014, 60, 858–871.
  52. Kim, D.; Kim, W.R.; Kim, H.J.; Therneau, T.M. Association between noninvasive fibrosis markers and mortality among adults with nonalcoholic fatty liver disease in the United States. Hepatology 2012, 57, 1357–1365.
  53. Adams, L.A.; Harmsen, S.; Sauver, J.S.; Charatcharoenwitthaya, P.; Enders, F.; Therneau, T.; Angulo, P. Nonalcoholic Fatty Liver Disease Increases Risk of Death among Patients with Diabetes: A Community-Based Cohort Study. Am. J. Gastroenterol. 2010, 105, 1567–1573.
  54. Targher, G.; Bertolini, L.; Rodella, S.; Zoppini, G.; Lippi, G.; Day, C.; Muggeo, M. Non-alcoholic fatty liver disease is independently associated with an increased prevalence of chronic kidney disease and proliferative/laser-treated retinopathy in type 2 diabetic patients. Diabetologia 2007, 51, 444–450.
  55. Adinolfi, L.E.; Petta, S.; Fracanzani, A.L.; Nevola, R.; Coppola, C.; Narciso, V.; Rinaldi, L.; Calvaruso, V.; Pafundi, P.C.; Lombardi, R.; et al. Reduced incidence of type 2 diabetes in patients with chronic hepatitis C virus infection cleared by direct-acting antiviral therapy: A prospective study. Diabetes Obes. Metab. 2020, 22, 2408–2416.
  56. Adinolfi, L.E.; Petta, S.; Fracanzani, A.L.; Coppola, C.; Narciso, V.; Nevola, R.; Rinaldi, L.; Calvaruso, V.; Staiano, L.; Di Marco, V.; et al. Impact of hepatitis C virus clearance by direct-acting antiviral treatment on the incidence of major cardiovascular events: A prospective multicentre study. Atherosclerosis 2020, 296, 40–47.
  57. Sasso, F.C.; Pafundi, P.C.; Caturano, A.; Galiero, R.; Vetrano, E.; Nevola, R.; Petta, S.; Fracanzani, A.L.; Coppola, C.; Di Marco, V.; et al. Impact of direct acting antivirals (DAAs) on cardiovascular events in HCV cohort with pre-diabetes. Nutr. Metab. Cardiovasc. Dis. 2021, 31, 2345–2353.
  58. De Vries, M.; Westerink, J.; Kaasjager, K.H.A.H.; de Valk, H.W. Prevalence of Nonalcoholic Fatty Liver Disease (NAFLD) in Patients with Type 1 Diabetes Mellitus: A Systematic Review and Meta-Analysis. J. Clin. Endocrinol. Metab. 2020, 105, 3842–3853.
  59. Pinhas-Hamiel, O.; Levek-Motola, N.; Kaidar, K.; Boyko, V.; Tisch, E.; Mazor-Aronovitch, K.; Graf-Barel, C.; Landau, Z.; Lerner-Geva, L.; Ben-David, R.F. Prevalence of overweight, obesity and metabolic syndrome components in children, adolescents and young adults with type 1 diabetes mellitus. Diabetes/Metabolism Res. Rev. 2014, 31, 76–84.
  60. Rewers, M.; Ludvigsson, J. Environmental risk factors for type 1 diabetes. Lancet 2016, 387, 2340–2348.
  61. Censin, J.C.; Nowak, C.; Cooper, N.; Bergsten, P.; Todd, J.A.; Fall, T. Childhood adiposity and risk of type 1 diabetes: A Mendelian randomization study. PLoS Med. 2017, 14, e1002362.
  62. Yi, X.; Cai, X.; Wang, S.; Xiao, Y. Mechanisms of impaired pancreatic β-cell function in high-fat diet-induced obese mice: The role of endoplasmic reticulum stress. Mol. Med. Rep. 2020, 21, 2041–2050.
  63. Maahs, D.M.; West, N.A.; Lawrence, J.; Mayer-Davis, E.J. Epidemiology of Type 1 Diabetes. Endocrinol. Metab. Clin. N. Am. 2010, 39, 481–497.
  64. Mayer-Davis, E.J.; Lawrence, J.; Dabelea, D.; Divers, J.; Isom, S.; Dolan, L.; Imperatore, G.; Linder, B.; Marcovina, S.; Pettitt, D.J.; et al. Incidence Trends of Type 1 and Type 2 Diabetes among Youths, 2002–2012. N. Engl. J. Med. 2017, 376, 1419–1429.
  65. Chobot, A.; Polanska, J.; Brandt, A.; Deja, G.; Glowinska-Olszewska, B.; Pilecki, O.; Szadkowska, A.; Mysliwiec, M.; Jarosz-Chobot, P. Updated 24-year trend of Type 1 diabetes incidence in children in Poland reveals a sinusoidal pattern and sustained increase. Diabet. Med. 2017, 34, 1252–1258.
  66. Kondrashova, A.; Reunanen, A.; Romanov, A.; Karvonen, A.; Viskari, H.; Vesikari, T.; Ilonen, J.; Knip, M.; Hyöty, H. A six-fold gradient in the incidence of type 1 diabetes at the eastern border of Finland. Ann. Med. 2005, 37, 67–72.
  67. Leslie, R.D.; Palmer, J.; Schloot, N.C.; Lernmark, A. Diabetes at the crossroads: Relevance of disease classification to pathophysiology and treatment. Diabetologia 2015, 59, 13–20.
  68. Lu, J.; Guo, M.; Wang, H.; Pan, H.; Wang, L.; Yu, X.; Zhang, X. Association between Pancreatic Atrophy and Loss of Insulin Secretory Capacity in Patients with Type 2 Diabetes Mellitus. J. Diabetes Res. 2019, 2019, 6371231.
  69. Regnell, S.E.; Lernmark, A. Hepatic Steatosis in Type 1 Diabetes. Rev. Diabet. Stud. 2011, 8, 454–467.
  70. Stadler, M.; Anderwald, C.; Pacini, G.; Zbýň, Š.; Promintzer-Schifferl, M.; Mandl, M.; Bischof, M.; Gruber, S.; Nowotny, P.; Luger, A.; et al. Chronic Peripheral Hyperinsulinemia in Type 1 Diabetic Patients After Successful Combined Pancreas-Kidney Transplantation Does Not Affect Ectopic Lipid Accumulation in Skeletal Muscle and Liver. Diabetes 2009, 59, 215–218.
  71. Bumbu, A.; Moutairou, A.; Matar, O.; Fumeron, F.; Velho, G.; Riveline, J.; Gautier, J.; Marre, M.; Roussel, R.; Potier, L. Non-severe hypoglycaemia is associated with weight gain in patients with type 1 diabetes: Results from the Diabetes Control and Complication Trial. Diabetes Obes. Metab. 2017, 20, 1289–1292.
  72. Han, H.-S.; Kang, G.; Kim, J.S.; Choi, B.H.; Koo, S.-H. Regulation of glucose metabolism from a liver-centric perspective. Exp. Mol. Med. 2016, 48, e218.
  73. Zhang, X.; Yang, S.; Chen, J.; Su, Z. Unraveling the Regulation of Hepatic Gluconeogenesis. Front. Endocrinol. 2019, 9, 802.
  74. Bergsten, P. Pathophysiology of Impaired Pulsatile Insulin Release. Diabetes/Metab. Res. Rev. 2000, 16, 179–191.
  75. Eslam, M.; George, J. Genetic contributions to NAFLD: Leveraging shared genetics to uncover systems biology. Nat. Rev. Gastroenterol. Hepatol. 2019, 17, 40–52.
  76. Wang, C.-M.; Yuan, R.-S.; Zhuang, W.-Y.; Sun, J.-H.; Wu, J.-Y.; Li, H.; Chen, J.-G. Schisandra polysaccharide inhibits hepatic lipid accumulation by downregulating expression of SREBPs in NAFLD mice. Lipids Health Dis. 2016, 15, 195.
  77. Iizuka, K.; Takao, K.; Yabe, D. ChREBP-Mediated Regulation of Lipid Metabolism: Involvement of the Gut Microbiota, Liver, and Adipose Tissue. Front. Endocrinol. 2020, 11, 587189.
  78. Meyer, G.; Dauth, N.; Grimm, M.; Herrmann, E.; Bojunga, J.; Friedrich-Rust, M. Shear Wave Elastography Reveals a High Prevalence of NAFLD-related Fibrosis Even in Type 1 Diabetes. Exp. Clin. Endocrinol. Diabetes 2021.
  79. Harman, D.J.; Kaye, P.V.; Harris, R.; Suzuki, A.; Gazis, A.; Aithal, G.P. Prevalence and natural history of histologically proven chronic liver disease in a longitudinal cohort of patients with type 1 diabetes. Hepatology 2014, 60, 158–168.
  80. Targher, G.; Bertolini, L.; Chonchol, M.; Rodella, S.; Zoppini, G.; Lippi, G.; Zenari, L.; Bonora, E. Non-alcoholic fatty liver disease is independently associated with an increased prevalence of chronic kidney disease and retinopathy in type 1 diabetic patients. Diabetologia 2010, 53, 1341–1348.
  81. Kasper, P.; Martin, A.; Lang, S.; Kütting, F.; Goeser, T.; Demir, M.; Steffen, H.-M. NAFLD and cardiovascular diseases: A clinical review. Clin. Res. Cardiol. 2020, 110, 921–937.
  82. Simon, T.G.; Roelstraete, B.; Khalili, H.; Hagström, H.; Ludvigsson, J.F. Mortality in biopsy-confirmed nonalcoholic fatty liver disease: Results from a nationwide cohort. Gut 2020, 70, 1375–1382.
  83. Fajans, S.S.; Conn, J.W. Tolbutamide-induced Improvement in Carbohydrate Tolerance of Young People with Mild Diabetes Mellitus. Diabetes 1960, 9, 83–88.
  84. Fajans, S.S.; Brown, M.B. Administration of Sulfonylureas Can Increase Glucose-Induced Insulin Secretion for Decades in Patients with Maturity-Onset Diabetes of the Young. Diabetes Care 1993, 16, 1254–1261.
  85. Shields, B.; Hicks, S.; Shepherd, M.; Colclough, K.; Hattersley, A.T.; Ellard, S. Maturity-onset diabetes of the young (MODY): How many cases are we missing? Diabetologia 2010, 53, 2504–2508.
  86. Estalella, I.; Rica, I.; de Nanclares, G.P.; Bilbao, J.R.; Vazquez, J.A.; Pedro, J.I.S.; Busturia, M.A.; Castaño, L. Spanish MODY Group Mutations in GCK and HNF-1? explain the majority of cases with clinical diagnosis of MODY in Spain. Clin. Endocrinol. 2007, 67, 538–546.
  87. Costa, A.; Bescós, M.; Velho, G.; Chevre, J.; Vidal, J.; Sesmilo, G.; Bellanne-Chantelot, C.; Froguel, P.; Casamitjana, R.; Rivera-Fillat, F.; et al. Genetic and clinical characterisation of maturity-onset diabetes of the young in Spanish families. Eur. J. Endocrinol. 2000, 142, 380–386.
  88. Shepherd, M.; Shields, B.; Ellard, S.; Rubio-Cabezas, O.; Hattersley, A.T. A genetic diagnosis of HNF1A diabetes alters treatment and improves glycaemic control in the majority of insulin-treated patients. Diabet. Med. 2009, 26, 437–441.
  89. Eide, S.; Ræder, H.; Johansson, S.; Midthjell, K.; Søvik, O.; Njølstad, P.R.; Molven, A. Prevalence ofHNF1A(MODY3) mutations in a Norwegian population (the HUNT2 Study). Diabet. Med. 2008, 25, 775–781.
  90. Sperling, M.A.; Garg, A. Monogenic Forms of Diabetes. In Diabetes in America, 3rd ed.; National Institute of Diabetes and Digestive and Kidney Diseases (US); Cowie, C.C., Casagrande, S.S., Menke, A., Cissell, M.A., Eberhardt, M.S., Meigs, J.B., Gregg, E.W., Eds.; Bethesda: Rockville, MD, USA, 2018. Available online: http://www.ncbi.nlm.nih.gov/books/NBK567994/ (accessed on 15 April 2022).
  91. Garg, A. Lipodystrophies: Genetic and Acquired Body Fat Disorders. J. Clin. Endocrinol. Metab. 2011, 96, 3313–3325.
  92. Polyzos, S.A.; Mantzoros, C.S. Lipodystrophy: Time for a global registry and randomized clinical trials to assess efficacy, safety and cost-effectiveness of established and novel medications. Metabolism 2017, 72, A4–A10.
  93. Fiorenza, C.G.; Chou, S.H.; Mantzoros, C.S. Lipodystrophy: Pathophysiology and advances in treatment. Nat. Rev. Endocrinol. 2010, 7, 137–150.
  94. Chan, J.L.; Oral, E.A. Clinical Classification and Treatment of Congenital and Acquired Lipodystrophy. Endocr. Pract. 2010, 16, 310–323.
  95. Zadeh, E.S.; Lungu, A.O.; Cochran, E.K.; Brown, R.; Ghany, M.G.; Heller, T.; Kleiner, D.; Gorden, P. The liver diseases of lipodystrophy: The long-term effect of leptin treatment. J. Hepatol. 2013, 59, 131–137.
  96. Araujo-Vilar, D.; Sánchez-Iglesias, S.; Guillín-Amarelle, C.; Castro, A.; Lage, M.; Pazos, M.; Rial, J.M.; Blasco, J.; Guillén-Navarro, E.; Domingo-Jiménez, R.; et al. Recombinant human leptin treatment in genetic lipodystrophic syndromes: The long-term Spanish experience. Endocrine 2014, 49, 139–147.
  97. Brown, R.J.; Meehan, C.A.; Cochran, E.; Rother, K.I.; Kleiner, D.E.; Walter, M.; Gorden, P. Effects of Metreleptin in Pediatric Patients with Lipodystrophy. J. Clin. Endocrinol. Metab. 2017, 102, 1511–1519.
  98. Brown, R.J.; Araujo-Vilar, D.; Cheung, P.T.; Dunger, D.; Garg, A.; Jack, M.; Mungai, L.; Oral, E.A.; Patni, N.; Rother, K.I.; et al. The Diagnosis and Management of Lipodystrophy Syndromes: A Multi-Society Practice Guideline. J. Clin. Endocrinol. Metab. 2016, 101, 4500–4511.
  99. Demir, T.; Onay, H.; Savage, D.B.; Temeloglu, E.; Uzum, A.K.; Kadioglu, P.; Altay, C.; Ozen, S.; Demir, L.; Cavdar, U.; et al. Familial partial lipodystrophy linked to a novel peroxisome proliferator activator receptor -γ (PPARG) mutation, H449L: A comparison of people with this mutation and those with classic codon 482 Lamin A/C (LMNA) mutations. Diabet. Med. 2016, 33, 1445–1450.
  100. Fajans, S.S. The definition of chemical diabetes. Metabolism 1973, 22, 211–217.
  101. Tattersall, R.B.; Mansell, P.I. Maturity Onset-type Diabetes of the Young (MODY): One Condition or Many? Diabet. Med. 1991, 8, 402–410.
  102. Rafique, I.; Mir, A.; Saqib, M.A.N.; Naeem, M.; Marchand, L.; Polychronakos, C. Causal variants in Maturity Onset Diabetes of the Young (MODY)—A systematic review. BMC Endocr. Disord. 2021, 21, 223.
  103. Pihoker, C.; Gilliam, L.K.; Ellard, S.; Dabelea, D.; Davis, C.; Dolan, L.M.; Greenbaum, C.J.; Imperatore, G.; Lawrence, J.M.; Marcovina, S.M.; et al. Prevalence, Characteristics and Clinical Diagnosis of Maturity Onset Diabetes of the Young Due to Mutations in HNF1A, HNF4A, and Glucokinase: Results from the SEARCH for Diabetes in Youth. J. Clin. Endocrinol. Metab. 2013, 98, 4055–4062.
  104. McDonald, T.; Ellard, S. Maturity onset diabetes of the young: Identification and diagnosis. Ann. Clin. Biochem. Int. J. Lab. Med. 2013, 50, 403–415.
  105. Broome, D.T.; Pantalone, K.M.; Kashyap, S.R.; Philipson, L.H. Approach to the Patient with MODY-Monogenic Diabetes. J. Clin. Endocrinol. Metab. 2020, 106, 237–250.
  106. Roehlen, N.; Hilger, H.; Stock, F.; Gläser, B.; Guhl, J.; Schmitt-Graeff, A.; Seufert, J.; Laubner, K. 17q12 Deletion Syndrome as a Rare Cause for Diabetes Mellitus Type MODY5. J. Clin. Endocrinol. Metab. 2018, 103, 3601–3610.
  107. Mateus, J.C.; Rivera, C.; O’Meara, M.; Valenzuela, A.; Lizcano, F. Maturity-onset diabetes of the young type 5 a MULTISYSTEMIC disease: A CASE report of a novel mutation in the HNF1B gene and literature review. Clin. Diabetes Endocrinol. 2020, 6, 16.
  108. Clissold, R.L.; Hamilton, A.J.; Hattersley, A.T.; Ellard, S.; Bingham, C. HNF1B-associated renal and extra-renal disease—an expanding clinical spectrum. Nat. Rev. Nephrol. 2014, 11, 102–112.
  109. Winter, W.E.; MacLaren, N.K.; Riley, W.J.; Clarke, D.W.; Kappy, M.S.; Spillar, R.P. Maturity-Onset Diabetes of Youth in Black Americans. N. Engl. J. Med. 1987, 316, 285–291.
  110. Umpierrez, G.; Casals, M.M.C.; Gebhart, S.S.P.; Mixon, P.S.; Clark, W.S.; Phillips, L. Diabetic Ketoacidosis in Obese African-Americans. Diabetes 1995, 44, 790–795.
  111. Umpierrez, G.; Woo, W.; Hagopian, W.; Isaacs, S.D.; Palmer, J.P.; Gaur, L.K.; Nepom, G.T.; Clark, W.S.; Mixon, P.S.; Kitabchi, A. Immunogenetic analysis suggests different pathogenesis for obese and lean African-Americans with diabetic ketoacidosis. Diabetes Care 1999, 22, 1517–1523.
  112. McFarlane, S.I.; Chaiken, R.L.; Hirsch, S.; Harrington, P.; Lebovitz, H.E.; Banerji, M.A. Near-normoglycaemic remission in African-Americans with Type 2 diabetes mellitus is associated with recovery of beta cell function. Diabet. Med. 2001, 18, 10–16.
  113. Sobngwi, E.; Vexiau, P.; Lévy, V.; Lepage, V.; Mauvais-Jarvis, F.; Leblanc, H.; Mbanya, J.C.; Gautier, J.F. Metabolic and immunogenetic prediction of long-term insulin remission in African patients with atypical diabetes. Diabet. Med. 2002, 19, 832–835.
  114. Kahn, S.E. The Importance of β-Cell Failure in the Development and Progression of Type 2 Diabetes. J. Clin. Endocrinol. Metab. 2001, 86, 4047–4058.
  115. Ladwa, M.; Bello, O.; Hakim, O.; Shojaee-Moradie, F.; Boselli, M.L.; Charles-Edwards, G.; Peacock, J.; Umpleby, A.M.; Amiel, S.A.; Bonadonna, R.C.; et al. Ethnic differences in beta cell function occur independently of insulin sensitivity and pancreatic fat in black and white men. BMJ Open Diabetes Res. Care 2021, 9, e002034.
  116. Mauvais-Jarvis, F.; Sobngwi, E.; Porcher, R.; Riveline, J.-P.; Kevorkian, J.-P.; Vaisse, C.; Charpentier, G.; Guillausseau, P.-J.; Vexiau, P.; Gautier, J.-F. Ketosis-Prone Type 2 Diabetes in Patients of Sub-Saharan African Origin: Clinical Pathophysiology and Natural History of Beta-Cell Dysfunction and Insulin Resistance. Diabetes 2004, 53, 645–653.
  117. Banerji, M.A.; Chaiken, R.L.; Huey, H.; Tuomi, T.; Norin, A.J.; Mackay, I.R.; Rowley, M.J.; Zimmet, P.Z.; E Lebovitz, H. GAD Antibody Negative NIDDM in Adult Black Subjects with Diabetic Ketoacidosis and Increased Frequency of Human Leukocyte Antigen DR3 and DR4: Flatbush Diabetes. Diabetes 1994, 43, 741–745.
  118. Banerji, M.A.; Lebovitz, H.E. Remission in Non-Insulin-Dependent Diabetes Mellitus: Clinical Characteristics of Remission and Relapse in Black Patients. Medicine 1990, 69, 176–185.
  119. Umpierrez, G.E.; Kelly, J.P.; Navarrete, J.E.; Casals, M.M.; Kitabchi, A.E. Hyperglycemic Crises in Urban Blacks. Arch. Intern. Med. 1997, 157, 669–675.
  120. Piñero-Piloña, A.; Raskin, P. Idiopathic Type 1 diabetes. J. Diabetes Its Complicat. 2001, 15, 328–335.
  121. Ansell, D.A.; Dodge, J.S.; Stewart, J. Geographic Patterns of Disease. N. Zealand Med. J. 1976, 83, 404–406.
  122. Yamada, K.; Nonaka, K. Diabetic Ketoacidosis in Young Obese Japanese Men. Diabetes Care 1996, 19, 671.
  123. Tan, K.C.; Mackay, I.R.; Zimmet, P.Z.; Hawkins, B.R.; Lam, K.S. Metabolic and immunologic features of Chinese patients with atypical diabetes mellitus. Diabetes Care 2000, 23, 335–338.
  124. Yan, S.-H.; Sheu, W.H.-H.; Song, Y.-M.; Tseng, L.-N. The Occurrence of Diabetic Ketoacidosis in Adults. Intern. Med. 2000, 39, 10–14.
  125. Yu, E.H.; Guo, H.-R.; Wu, T.-J. Factors associated with discontinuing insulin therapy after diabetic ketoacidosis in adult diabetic patients. Diabet. Med. 2001, 18, 895–899.
  126. Fajans, S.S.; Bell, G.I. MODY. Diabetes Care 2011, 34, 1878–1884.
  127. Mohanty, S.R.; Troy, T.N.; Huo, D.; O’Brien, B.L.; Jensen, D.M.; Hart, J. Influence of ethnicity on histological differences in non-alcoholic fatty liver disease. J. Hepatol. 2009, 50, 797–804.
  128. Bril, F.; Portillo-Sanchez, P.; Liu, I.-C.; Kalavalapalli, S.; Dayton, K.; Cusi, K. Clinical and Histologic Characterization of Nonalcoholic Steatohepatitis in African American Patients. Diabetes Care 2017, 41, 187–192.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)
Video Production Service
Feedback