The first series of cases of ketosis-prone type 2 diabetes (flatbush diabetes) in Brazilian adults

Luana Aparecida de Lima Ramaldes Sarah Simaan dos Santos João Roberto de Sa Patrícia Médici Dualib Sérgio Atala Dib About the authors

SUMMARY

Ketosis-prone type 2 diabetes (KPD) is an emerging form of diabetes mellitus characterized by unprovoked ketoacidosis, absence of autoimmunity and beta-cell dysfunction. The KPD may improve after initial glycemic compensation and evolve to exogenous insulin independence, most cases were observed in populations with African or Hispanic backgrounds. We reviewed the literature on KPD and, to date, only one case of KPD has been described in Brazil's multi-ethnic population. A group of adult Brazilian KPD patients without autoimmunity and insulinopenia was identified for this study. We report a retrospective study of four KPD cases (3 males) evaluated in southeast Brazil, the patients were overweight or obese, age between the third and fifth decades of life, had a family history of type 2 diabetes, hyperglycemia (809.5 ± 344.2 mg/dL), acidosis (pH 7.21 ± 0.07; normal range (nr): 7.35-7.45 and bicarbonate 9.1 ± 6.2; nr: 22-26 mEq/mL), ketonuria (142.5 ± 114.4 mg/dL; nr: absence), absence of glutamic acid decarboxylase antibodies (GAD-65), and beta-cell function reserve (C-peptide 1.19 ± 0.53 ng/mL - nr: 1.1-4.4 ng/mL) on diagnosis. After glycemic compensation, there was increase of C-peptide (2.21 ± 0.41) indicating the recovery of beta-cell function and the time to insulin independence was 7.7 ± 3.5 months. They evolved after the period of glucotoxicity with insulin withdrawal and could be treated with oral antidiabetic therapy. This is the first case series of KPD described in Brazil being characterized by ketoacidosis at diagnosis, absence of autoimmunity, recovery of beta-cell function and insulin independence.

INTRODUCTION

Diabetes mellitus (DM) comprises a group of metabolic diseases characterized by hyperglycemia resulting from a defect in insulin secretion, insulin action, or both. Diabetes Mellitus that emerges with ketoacidosis in adults may correspond to a heterogeneous group of diseases with different etiologies (11. Umpierrez GE, Casals MMC, Gebhart SSP, Mixon PS, Scott Clark W, Phillips LS. Diabetic ketoacidosis in obese African-Americans. Diabetes. 1995;44(7):790-5.55. Winter WE, Maclaren NK, Riley WJ, Clarke DW, Kappy MS, Spillar RP. Maturity-Onset Diabetes of Youth in Black Americans. N Engl J Med. 1987 Feb 5;316(6):285-91.). One of these pathologies, ketosis-prone type 2 diabetes (KPD), is associated with severe hyperglycemia and ketoacidosis on presentation, followed by remission after insulin therapy (55. Winter WE, Maclaren NK, Riley WJ, Clarke DW, Kappy MS, Spillar RP. Maturity-Onset Diabetes of Youth in Black Americans. N Engl J Med. 1987 Feb 5;316(6):285-91.,66. Sobngwi E, Mauvais-Jarvis F, Vexiau P, Mbanya JC, Gautier JF. Diabetes in Africans. Part 2: Ketosis-prone atypical diabetes mellitus. Diabetes Metab. 2002 Feb;28(1):5-12.). After weeks or months, these patients can discontinue insulin and maintain glycemic control using diet or oral agents or both. These patients do not have anti-islet autoantibodies, but may have some common type 1 diabetes susceptibility HLA alleles (77. Nalini R, Gaur LK, Maldonado M, Hampe CS, Rodriguez L, Garza G, et al. HLA class II alleles specify phenotypes of ketosis-prone diabetes. Diabetes Care. 2008 Jun;31(6):1195-200.,88. Banerji MA, Chaiken RL, Huey H, Tuomi T, Norin AJ, Mackay IR, et al. 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(6):741-5.).

Ketosis-prone diabetes mellitus was initially described in the 1960s in the United States (99. Dodu SR. Diabetes in the tropics. Br Med J. 1967 Jun;2(5554):747-50.), followed by reports in Africa, Japan, Spain, China, and Pakistan, suggesting a global distribution of the disease (22. Maldonado M, Hampe CS, Gaur LK, D’Amico S, Iyer D, Hammerle LP, et al. Ketosis-prone diabetes: dissection of a heterogeneous syndrome using an immunogenetic and beta-cell functional classification, prospective analysis, and clinical outcomes. J Clin Endocrinol Metab. 2003 Nov;88(11):5090-8.). The prevalence of KPD cases is higher in African Americans and Hispanics than in Caucasians and Asians (1010. Smiley D, Chandra P, Umpierrez GE. Update on diagnosis, pathogenesis and management of ketosis-prone Type 2 diabetes mellitus. Diabetes Manag. 2011;1(6):589-600.). In addition, is also an important differential diagnosis among individuals classified as having adult type 1 diabetes, as it affects individuals over 30 years old, often with the first decompensation in ketoacidosis.

In Brazil, the population has a multi-ethnic origin, with over 70% of the population composed of Europeans and Africans descendants (1111. Gomes MB, Gabrielli AB, Santos DC, Pizarro MH, Barros BSV, Negrato CA, et al. Self-reported color-race and genomic ancestry in an admixed population: A contribution of a nationwide survey in patients with type 1 diabetes in Brazil. Diabetes Res Clin Pract. 2018 Jun;140:245-52.). Nevertheless, despite the population's African background and the importance of patients and clinicians’ recognition and understanding of this type of diabetes, the Brazilian national literature contains only one case reported of KPD (1212. Rodacki M, Zajdenverg L, Lima GAB, Nunes RC, Milech A, De Oliveira JEP. Relato de caso: Diabetes Flatbush – Da cetoacidose ao tratamento não-farmacológico. Arq Bras Endocrinol Metabol. 2007;51(1):131-5.). We report a retrospective study of a series of cases and a literature review of KPD.

DESCRIPTION OF CASES

General characteristics

The patients were recruited from March to November 2018 by retrospective data analysis of the last 6 years, all patients were followed in the Diabetes Center of the Federal University of São Paulo, Brazil. The literature review and data reassessment were carried out in March 2020. The KPD diagnosis was based on the occurrence of spontaneous severe ketoacidosis in individuals with diabetes diagnosis not classifiable in the classic diabetes types, age above 30 years, absence of antiglutamic acid decarboxylase antibodies (GAD-65) and beta-cell function reserve after correction of ketoacidosis (fasting C-peptide level least 1 ng/mL; normal range [nr]: 1.1-4.4 ng/mL; immunofluorometric assay (Auto Delfia, Finland) with a detection limit of 0.10 ng/mL), criteria previously established by Maldonado and cols. (22. Maldonado M, Hampe CS, Gaur LK, D’Amico S, Iyer D, Hammerle LP, et al. Ketosis-prone diabetes: dissection of a heterogeneous syndrome using an immunogenetic and beta-cell functional classification, prospective analysis, and clinical outcomes. J Clin Endocrinol Metab. 2003 Nov;88(11):5090-8.). The diagnosis of ketoacidosis was defined as a blood pH ≤ 7.3 within the first 24h, with positive urine ketones. The institution's ethics committee approved the study (CAAE NUMBER: 96720818.6.0000.5505), and informed consent term were obtained from the participants.

The general clinical and biochemical characteristics of the studied patients appear in Table 1, and follow-up data in Table 2.

Table 1
Clinical and biochemical characteristics at diagnosis of ketosis prone diabetes in Brazilian patients
Table 2
Current treatment of ketosis prone diabetes in Brazilian patients

CASE 1

A 48-year-old male who was diagnosed with diabetes mellitus at age 45 presented in our emergency room with symptoms of glycemic decompensation (polydipsia, polyuria, and weight loss). His laboratory tests revealed hyperglycemia (922 mg/dL), acidosis (pH 7.28; nr: 7.35-7.45) and ketonuria positive without an identified triggering factor. His glycosylated hemoglobin (HbA1c) was 14.3%, and he had hypertriglyceridemia (TG:1129 mg/dL). Pancreatitis was excluded based on the clinical picture and normal values of lipase and amylase in his blood. Regarding the etiological diabetes investigation, GAD-65 autoantibody was negative, and the patient's fasting C-peptide level was 0.70 ng/mL. During his first outpatient clinic visit, he denied previous comorbidities but indicated a family history of two generations affected by DM. Physical examination revealed a BMI of 39.9 kg/m2 and severe cervical acanthosis. After 8 weeks of insulin treatment, he began to present episodes of hypoglycemia and required a reduction of the initial insulin dose. After 12 weeks of follow-up, his laboratory tests revealed: HbA1c 6.1%, fasting C-peptide level 1.21 ng/mL. Due to the absence of GAD-65 autoantibodies and fasting C-peptide elevation after improved glycemic control, there was suspicion of KPD, thus his treatment was modified for metformin and lifestyle changes. Tables 1 and 2 summarize these data.

CASE 2

A 51-year-old male was monitored in the Diabetes Center's outpatient clinic since the diagnosis of diabetic ketoacidosis (Table 1) at age 48 [HbA1c 17.1%, GAD-65 autoantibody negative, and fasting C-peptide level 1.03 ng/mL], without triggering factor identified. Regarding antecedents, he indicated an absence of comorbidities except social alcohol consumption and a family history of DM. On physical examination, he presented a BMI of 25.5 kg/m2 without other significant abnormalities. After 9 weeks of insulin treatment, he began to have episodes of hypoglycemia, so we began a progressive reduction of his insulin dose. After 16 weeks of treatment, his HbA1c was 6.4%, and fasting C-peptide level was 1.38 ng/mL. Six months later, the insulin therapy was stopped, and he started 500 mg of metformin and 30 mg of gliclazide per day. So far, he is doing well during follow-up.

CASE 3

A 45-year-old male in follow-up at the Diabetes Center's outpatient clinic referred to the diagnosis of DM at age 42 when presenting symptoms of glycemic decompensation (polydipsia, polyuria, and weight loss) and unprovoked ketoacidosis. At diagnosis, his laboratory exams revealed blood glucose 1221 mg/dL, HbA1c 15.1%, high lipids (total cholesterol – 334 mg/dL); triglycerides: 742 mg/dL), fasting C-peptide level 1.09 ng/mL, and GAD-65 autoantibodies negative. He referred to a previous diagnosis of systemic arterial hypertension and a family history of DM. Physical examination showed a BMI of 28.4 kg/m2 and mild cervical acanthosis nigricans. After 9 weeks of treatment, the doses of insulin necessary to establish glycemic control began to decrease, and after 18 weeks, his HbA1c had decreased to 7.8% and his fasting C-peptide level had increased to 4.5ng/mL. At his last appointment, he was on basal insulin (0.5U/kg/day) plus metformin (1.7 g/day) and atorvastatin (10 mg/day).

CASE 4

A 36-year-old female had been undergoing follow-up at the Diabetes Center outpatient clinic since her DM diagnosis. She was diagnosed at age 30, presenting symptoms of glycemic decompensation (polydipsia, polyuria, and weight loss), acidosis, and ketonuria, without an identified triggering factor (Table 1). At diagnosis, her exams test revealed: HbA1c 10.5%, negative for GAD-65 autoantibodies and fasting C-peptide 1.96 ng/mL. During her first outpatient clinic visit, she indicated no history of previous comorbidities, but mentioned a family member with a recent DM diagnosis. On physical examination, she presented a BMI of 30.3 kg/m2 and moderate cervical acanthosis nigricans. After 8 weeks of insulin treatment, she began to present periods of hypoglycemia, so her insulin daily dose was decreased. After 12 months, insulin was discontinued. By this time, her exam tests revealed: HbA1c 6.2%, fasting C-peptide 1.9 ng/mL and post-prandial C-peptide level was 7.2 ng/mL, thus her treatment was modified for 850 mg of metformin and 60 mg of gliclazide per day. This patient maintained oral antidiabetic treatment for 2 years, after that time the medications were withdrawn, and she got good glycemic control only with diet and exercise. However, in last year, she presented some episodes suggestive of minor ketosis hyperglycemia decompensation, making it necessary guidelines for its correction with insulin and prescription of oral medication. A resume of the four patients’ current treatment is shown in Table 2.

In summary, the initial treatment of all patients included insulin, which was discontinued after periods varying from 4 to 12 months, with exception of one patient who required a low dose of insulin for maintenance after initial compensation.

DISCUSSION

Ketosis-prone diabetes is being recognized worldwide. A review of the theme demonstrates the prevalence according to ethnicity, with a high risk of occurrence in the African American and Hispanic populations and low risk in Caucasian and Asian populations (1010. Smiley D, Chandra P, Umpierrez GE. Update on diagnosis, pathogenesis and management of ketosis-prone Type 2 diabetes mellitus. Diabetes Manag. 2011;1(6):589-600.), but data are insufficient to define the exact prevalence. In Brazil, a recent study showed that the Brazilian population has a predominance of European and African ancestry (1111. Gomes MB, Gabrielli AB, Santos DC, Pizarro MH, Barros BSV, Negrato CA, et al. Self-reported color-race and genomic ancestry in an admixed population: A contribution of a nationwide survey in patients with type 1 diabetes in Brazil. Diabetes Res Clin Pract. 2018 Jun;140:245-52.), but only one case report (1212. Rodacki M, Zajdenverg L, Lima GAB, Nunes RC, Milech A, De Oliveira JEP. Relato de caso: Diabetes Flatbush – Da cetoacidose ao tratamento não-farmacológico. Arq Bras Endocrinol Metabol. 2007;51(1):131-5.) of KPD in more than a decade, so this type of diabetes may be underdiagnosed in Brazil.

Here we present a series of cases of KPD cases from southeast Brazil. The diagnosis was made in overweight or obese males between the third and fifth decades of life with characteristics comparable to African, Hispanic, Caucasian, and Asian American individuals.

These patients’ most important phenotypic characteristics include spontaneous ketoacidosis, but the mechanisms responsible for this unprovoked ketoacidosis are not completely known. At least five important abnormalities have been discussed in this respect: A) pancreatic beta-cell function is very sensitive to glucotoxicity (1313. Weir GC, Marselli L, Marchetti P, Katsuta H, Jung MH, Bonner-Weir S. Towards better understanding of the contributions of overwork and glucotoxicity to the β-cell inadequacy of type 2 diabetes. Diabetes, Obes Metab. 2009;11(Suppl. 4):82-90.) because of the low expression of antioxidant enzymes necessary for the elimination of reactive oxygen species; B) there is a higher prevalence of G6PD deficiency (related to anti-oxidant defense) in KPD compared with controls and patients with classical type 2 diabetes (1414. Sobngwi E, Gautier J-F, Kevorkian J-P, Villette J-M, Riveline J-P, Zhang S, et al. High Prevalence of Glucose-6-Phosphate Dehydrogenase Deficiency without Gene Mutation Suggests a Novel Genetic Mechanism Predisposing to Ketosis-Prone Diabetes. J Clin Endocrinol Metab. 2005 Sep 1;90:4446-51.); C) alpha-cell dysfunction is similar to classical type 2 diabetes, resulting in inappropriate secretion of glucagon (1515. Choukem S-P, Sobngwi E, Boudou P, Fetita L-S, Porcher R, Ibrahim F, et al. β- and α-Cell Dysfunctions in Africans With Ketosis-Prone Atypical Diabetes During Near-Normoglycemic Remission. Diabetes Care. 2013 Jan 1;36(1):118-23.); D) ketolysis (clearance of ketone bodies) decreases (1616. Patel SG, Hsu JW, Jahoor F, Coraza I, Bain JR, Stevens RD, et al. Pathogenesis of A2b+ ketosis-prone diabetes. Diabetes. 2013 Mar 1;62(3):912-22.); and E) prolonged ketonemia per se could exert negative effects on beta-cell function in patients with KPD (1717. Zhou YP, Grill V. Long term exposure to fatty acids and ketones inhibits B-cell functions in human pancreatic islets of Langerhans. J Clin Endocrinol Metab. 1995 May 1;80(5):1584-90.).

The insulin resistance component in patients with KPD has also been discussed; some studies show that it can be important when evaluated shortly after the initial event but increases slightly or is persistent when associated with obesity after hyperglycemia resolution during follow-up (1414. Sobngwi E, Gautier J-F, Kevorkian J-P, Villette J-M, Riveline J-P, Zhang S, et al. High Prevalence of Glucose-6-Phosphate Dehydrogenase Deficiency without Gene Mutation Suggests a Novel Genetic Mechanism Predisposing to Ketosis-Prone Diabetes. J Clin Endocrinol Metab. 2005 Sep 1;90:4446-51.). All our patients had a family history of type 2 diabetes and presented clinical characteristics associated with insulin resistance, such as obesity and the presence of acanthosis nigricans. In addition, 3 of 4 had glycemia (> 500 mg/dL) and 2 of 4 had hypertriglyceridemia (> 500 mg/dL) at the time of diagnosis. This last found in our patients, in favor of insulin resistance was not highlighted in previous studies. This might collaborate to β dysfunction because some researchers suggest that a period of exposure to high levels of glucose and fatty acids can result in significant impairment of insulin secretion in individuals with a family history of type 2 diabetes (1818. Poitout V, Briaud I, Kelpe C, Hagman D. Gluco-lipotoxicity of the pancreatic beta cell. Ann Endocrinol (Paris). 2004 Feb;65(1):37-41.,1919. Kashyap S, Belfort R, Gastaldelli A, Pratipanawatr T, Berria R, Pratipanawatr W, et al. A sustained increase in plasma free fatty acids impairs insulin secretion in nondiabetic subjects genetically predisposed to develop type 2 diabetes. Diabetes. 2003 Oct;52(10):2461-74.). However, recent studies have shown that a decrease in beta-cell function during the acute phase of the disease is related more to the toxic effects of chronically elevated glucose levels (glucotoxicity) than to high lipid concentrations; in other words, pancreatic islet patients with KPD might have a resistance to lipotoxicity (1818. Poitout V, Briaud I, Kelpe C, Hagman D. Gluco-lipotoxicity of the pancreatic beta cell. Ann Endocrinol (Paris). 2004 Feb;65(1):37-41.).

With the improvement of hyperglycemia, we can detect the recovery of beta-cell function in our patients (3 of 4 patients had an increase of more than 100% in basal C-peptide levels on follow-up). Case 2 was the only patient who had a normal weight, lacked acanthosis nigricans, and had a high HbA1c level, at diagnosis, and experienced a smaller increase in insulin secretion (only 25% of basal) and normal lipid profile at follow-up (in opposition to insulin resistance).

Significant recovery of beta-cell function was reported, and insulin independence in the group was higher than 75%. Only Case 3 maintained the use of insulin to ensure adequate glycemic control, which is compatible with the findings of other studies that characterized a cohort of 223 KPD patients, only 23% of whom maintained insulin dependence (33. Mauvais-Jarvis F, Sobngwi EE, Porcher RR, Riveline J-PP, Kevorkian J-PP, Vaisse C, et al. 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 Mar;53(3):645-53.). However, the persistence of residual insulin beta-cell secretions for more than 3 years of DM diagnosis was observed in all our patients.

Given the discussion above and given that the expression of those conditions are variable in KPD, after the resolution of beta-cell glucotoxicity, treatment with oral medications commonly used in type 2 DM is possible.

In our study, the use of insulin, metformin, and sulfonylurea (gliclazide) stands out mainly due to the limitation of low-cost antidiabetic drugs available at our public hospital, but so far as possible get a satisfactory glycemic control.

Reported cases describe the use of modern therapies such as DPP4 inhibitors, SGLT2 transporter inhibitors, and GLP1 analogs (2020. Sjoholm A. Ketosis-Prone Type 2 Diabetes: A Case Series. Vol. 10, Frontiers in endocrinology. Switzerland; 2019. p. 684.). Nevertheless, is important to mention that if SGLT2 transporter inhibitors are used in this group of patients, we must be cautious because these patients have an increased risk of ketoacidosis (1515. Choukem S-P, Sobngwi E, Boudou P, Fetita L-S, Porcher R, Ibrahim F, et al. β- and α-Cell Dysfunctions in Africans With Ketosis-Prone Atypical Diabetes During Near-Normoglycemic Remission. Diabetes Care. 2013 Jan 1;36(1):118-23.) which is a possible complication of these drugs due to various pathophysiological mechanisms (2121. Lebovitz HE, Banerji MA. Ketosis-Prone Diabetes (Flatbush Diabetes): an Emerging Worldwide Clinically Important Entity. Curr Diab Rep. 2018;18(11):120.). These include increased glucagon secretion and the consequent rise in lipolysis and ketogenesis, as well as the reduction in renal ketone clearance.

CONCLUSIONS

This is the first case series of KPD described in Brazilian adult with diabetes mellitus. We show that these patients classified as having atypical diabetes could also occur in the Brazilian population. KPD manifests not due to a loss of beta-cell mass, but a transitory failure of these cells to respond to hyperglycemia. Further studies are necessary to verify the prevalence of this subtype of diabetes in the Brazilian population. Therefore, when ketosis is present at diagnosis, in the absence of autoimmunity and the presence of beta-cell function, patients may be able to discontinue insulin and maintain glycemic control using appropriate diet, exercise, and oral hypoglycemic agents in follow-up.

  • Patient consent: written informed consent was obtained from the patient for publication of the submitted article.
  • Funding: this research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

REFERENCES

  • 1
    Umpierrez GE, Casals MMC, Gebhart SSP, Mixon PS, Scott Clark W, Phillips LS. Diabetic ketoacidosis in obese African-Americans. Diabetes. 1995;44(7):790-5.
  • 2
    Maldonado M, Hampe CS, Gaur LK, D’Amico S, Iyer D, Hammerle LP, et al. Ketosis-prone diabetes: dissection of a heterogeneous syndrome using an immunogenetic and beta-cell functional classification, prospective analysis, and clinical outcomes. J Clin Endocrinol Metab. 2003 Nov;88(11):5090-8.
  • 3
    Mauvais-Jarvis F, Sobngwi EE, Porcher RR, Riveline J-PP, Kevorkian J-PP, Vaisse C, et al. 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 Mar;53(3):645-53.
  • 4
    Balasubramanyam A, Nalini R, Hampe CS, Maldonado M. Syndromes of ketosis-prone diabetes mellitus. Endocr Rev. 2008;29(3):292-302.
  • 5
    Winter WE, Maclaren NK, Riley WJ, Clarke DW, Kappy MS, Spillar RP. Maturity-Onset Diabetes of Youth in Black Americans. N Engl J Med. 1987 Feb 5;316(6):285-91.
  • 6
    Sobngwi E, Mauvais-Jarvis F, Vexiau P, Mbanya JC, Gautier JF. Diabetes in Africans. Part 2: Ketosis-prone atypical diabetes mellitus. Diabetes Metab. 2002 Feb;28(1):5-12.
  • 7
    Nalini R, Gaur LK, Maldonado M, Hampe CS, Rodriguez L, Garza G, et al. HLA class II alleles specify phenotypes of ketosis-prone diabetes. Diabetes Care. 2008 Jun;31(6):1195-200.
  • 8
    Banerji MA, Chaiken RL, Huey H, Tuomi T, Norin AJ, Mackay IR, et al. 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(6):741-5.
  • 9
    Dodu SR. Diabetes in the tropics. Br Med J. 1967 Jun;2(5554):747-50.
  • 10
    Smiley D, Chandra P, Umpierrez GE. Update on diagnosis, pathogenesis and management of ketosis-prone Type 2 diabetes mellitus. Diabetes Manag. 2011;1(6):589-600.
  • 11
    Gomes MB, Gabrielli AB, Santos DC, Pizarro MH, Barros BSV, Negrato CA, et al. Self-reported color-race and genomic ancestry in an admixed population: A contribution of a nationwide survey in patients with type 1 diabetes in Brazil. Diabetes Res Clin Pract. 2018 Jun;140:245-52.
  • 12
    Rodacki M, Zajdenverg L, Lima GAB, Nunes RC, Milech A, De Oliveira JEP. Relato de caso: Diabetes Flatbush – Da cetoacidose ao tratamento não-farmacológico. Arq Bras Endocrinol Metabol. 2007;51(1):131-5.
  • 13
    Weir GC, Marselli L, Marchetti P, Katsuta H, Jung MH, Bonner-Weir S. Towards better understanding of the contributions of overwork and glucotoxicity to the β-cell inadequacy of type 2 diabetes. Diabetes, Obes Metab. 2009;11(Suppl. 4):82-90.
  • 14
    Sobngwi E, Gautier J-F, Kevorkian J-P, Villette J-M, Riveline J-P, Zhang S, et al. High Prevalence of Glucose-6-Phosphate Dehydrogenase Deficiency without Gene Mutation Suggests a Novel Genetic Mechanism Predisposing to Ketosis-Prone Diabetes. J Clin Endocrinol Metab. 2005 Sep 1;90:4446-51.
  • 15
    Choukem S-P, Sobngwi E, Boudou P, Fetita L-S, Porcher R, Ibrahim F, et al. β- and α-Cell Dysfunctions in Africans With Ketosis-Prone Atypical Diabetes During Near-Normoglycemic Remission. Diabetes Care. 2013 Jan 1;36(1):118-23.
  • 16
    Patel SG, Hsu JW, Jahoor F, Coraza I, Bain JR, Stevens RD, et al. Pathogenesis of A2b+ ketosis-prone diabetes. Diabetes. 2013 Mar 1;62(3):912-22.
  • 17
    Zhou YP, Grill V. Long term exposure to fatty acids and ketones inhibits B-cell functions in human pancreatic islets of Langerhans. J Clin Endocrinol Metab. 1995 May 1;80(5):1584-90.
  • 18
    Poitout V, Briaud I, Kelpe C, Hagman D. Gluco-lipotoxicity of the pancreatic beta cell. Ann Endocrinol (Paris). 2004 Feb;65(1):37-41.
  • 19
    Kashyap S, Belfort R, Gastaldelli A, Pratipanawatr T, Berria R, Pratipanawatr W, et al. A sustained increase in plasma free fatty acids impairs insulin secretion in nondiabetic subjects genetically predisposed to develop type 2 diabetes. Diabetes. 2003 Oct;52(10):2461-74.
  • 20
    Sjoholm A. Ketosis-Prone Type 2 Diabetes: A Case Series. Vol. 10, Frontiers in endocrinology. Switzerland; 2019. p. 684.
  • 21
    Lebovitz HE, Banerji MA. Ketosis-Prone Diabetes (Flatbush Diabetes): an Emerging Worldwide Clinically Important Entity. Curr Diab Rep. 2018;18(11):120.

Publication Dates

  • Publication in this collection
    05 Mar 2021
  • Date of issue
    Mar-Apr 2021

History

  • Received
    30 July 2020
  • Accepted
    10 Jan 2021
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