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Query: UMLS:C0011854 (type 1 diabetes)
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Ketosis-prone diabetes (KPD) is a rare form of type 2 diabetes, mostly observed in subjects of west African origin (west Africans and African-Americans), characterized by fulminant and phasic insulin dependence, but lacking markers of autoimmunity observed in type 1 diabetes. PAX4 is a transcription factor essential for the development of insulin-producing pancreatic beta-cells. Recently, a missense mutation (Arg121Trp) of PAX4 has been implicated in early and insulin deficient type 2 diabetes in Japanese subjects. The phenotype similarities between KPD and Japanese carriers of Arg121Trp have prompted us to investigate the role of PAX4 in KPD. We have screened 101 KPD subjects and we have found a new variant in the PAX4 gene (Arg133Trp), specific to the population of west African ancestry, and which predisposes to KPD under a recessive model. Homozygous Arg133Trp PAX4 carriers were found in 4% of subjects with KPD but not in 355 controls or 147 subjects with common type 2 or type 1 diabetes. In vitro, the Arg133Trp variant showed a decreased transcriptional repression of target gene promoters in an alpha-TC1.6 cell line. In addition, one KPD patient was heterozygous for a rare PAX4 variant (Arg37Trp) that was not found in controls and that showed a more severe biochemical phenotype than Arg133Trp. Clinical investigation of the homozygous Arg133Trp carriers and of the Arg37Trp carrier demonstrated a more severe alteration in insulin secretory reserve, during a glucagon-stimulation test, compared to other KPD subjects. Together these data provide the first evidence that ethnic-specific gene variants may contribute to the predisposition to this particular form of diabetes and suggest that KPD, like maturity onset diabetes of the young, is a rare, phenotypically defined but genetically heterogeneous form of type 2 diabetes.
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PMID:PAX4 gene variations predispose to ketosis-prone diabetes. 1550 90

This article proposes five stages in the progression of diabetes, each of which is characterized by different changes in beta-cell mass, phenotype, and function. Stage 1 is compensation: insulin secretion increases to maintain normoglycemia in the face of insulin resistance and/or decreasing beta-cell mass. This stage is characterized by maintenance of differentiated function with intact acute glucose-stimulated insulin secretion (GSIS). Stage 2 occurs when glucose levels start to rise, reaching approximately 5.0-6.5 mmol/l; this is a stable state of beta-cell adaptation with loss of beta-cell mass and disruption of function as evidenced by diminished GSIS and beta-cell dedifferentiation. Stage 3 is a transient unstable period of early decompensation in which glucose levels rise relatively rapidly to the frank diabetes of stage 4, which is characterized as stable decompensation with more severe beta-cell dedifferentiation. Finally, stage 5 is characterized by severe decompensation representing a profound reduction in beta-cell mass with progression to ketosis. Movement across stages 1-4 can be in either direction. For example, individuals with treated type 2 diabetes can move from stage 4 to stage 1 or stage 2. For type 1 diabetes, as remission develops, progression from stage 4 to stage 2 is typically found. Delineation of these stages provides insight into the pathophysiology of both progression and remission of diabetes.
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PMID:Five stages of evolving beta-cell dysfunction during progression to diabetes. 1556 5

In the Japanese population, the incidence of type 1 diabetes is as low as approximately 2 cases/year/100,000 children, which is much lower compared to that in countries with populations predominantly of Caucasian origin. However, the prevalences of anti-islet autoantibodies in patients with Japanese type 1 diabetes are 60-70% for GAD autoantibodies, 45-50% for insulin autoantibodies (IAA), and 60-65% for IA-2 autoantibodies at disease onset, which are similar to those reported in Caucasian patients. With combinatorial analysis of these autoantibodies, 90% of patients express at least one of these autoantibodies and are classified as type 1A diabetics. There is a significant number of patients with latent autoimmune diabetes in adults (LADA) in Japan, and a high level of GAD autoantibodies has a high predictive value for future insulin deficiency in such patients. Recently, it has been reported that a group of extremely rapid-onset patients presented with diabetic ketoacidosis and a low HbA1c level, called fulminant diabetes mellitus. Although they had severe hyperglycemia, these individuals lacked the expression of anti-islet autoantibodies. With a nationwide survey, it was documented that fulminant type 1 diabetes accounts for approximately 20% of the ketosis-onset patients with type 1 diabetes in Japan. It is currently unknown whether the pathogenesis of fulminant type 1 diabetes is associated with autoimmune response to pancreatic islet beta cells. Japanese patients with type 1 diabetes are clinically heterogeneous, and further investigations are required to clarify the underlying pathogenesis for each subgroup of type 1 diabetes.
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PMID:Is Type 1 diabetes in the Japanese population the same as among Caucasians? 1569 99

The study analyzed the clinical background and eating habits of Japanese youth-onset type 2 diabetes. Thirty-six patients with type 2 diabetes (22 males, 14 females) with onset in less than 20-year-old were studied. All patients were negative for anti-glutamic acid decarboxylase (GAD) antibody and islet cell antibody. Cases diagnosed as having abnormalities in the mitochondrial gene, maturity onset diabetes of the young (MODY), and apparent type 1 diabetes were excluded from the study. Urinary ketone was detected positive in 11 cases among 36 patients at the onset of diabetes. We compared the clinical characteristics and food compositions between the patients with ketonuria and those without ketonuria. Age and urinary C-peptide secretion did not show any significant difference between both groups. In the patients with ketonuria, male to female ratio was remarkably high (10:1) compared with the group without ketonuria (12:13). Positive diabetic family history was predominantly higher in the group with ketonuria (11/11) than that in the group without ketonuria (17/25). All these were identical to previously reported characteristics of soft-drink ketosis. However, we in this study, revealed the difference of total calorie intake and dietary composition between youth-onset type 2 diabetes with and without ketonuria. As a result dietary contents such as carbohydrate, fat and confectionery in the former group were also 1.5, 1.4-2.4 times higher, respectively, than those in the latter group.
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PMID:Clinical characteristics of Japanese youth-onset type 2 diabetes with ketonuria. 1594 60

Nonketotic hyperosmolar coma (NHC) is characterized by severe hyperglycemia; absence of, or only slight ketosis; nonketotic acidosis; severe dehydration; depressed sensorium or frank coma; and various neurologic signs. This condition is uncommon in type 1 diabetes. Because of little or no osmotic diuresis in patients with diabetic nephropathy, increases in plasma osmolality and therefore the likelihood of neurologic symptoms are limited. A 20-year-old male patient with type 1 diabetes with chronic kidney disease on conservative treatment (glomerular filtration rate [GFR], 18 mL/dk) presented with acute nonketotic hyperosmolar syndrome. The patient was admitted presenting with thirst, fatigue, and drowsiness. Blood biochemistry levels were urea 87 mg/dL, creatinine 5.09 mg/dL, glucose 830 mg/dL, glycosylated hemoglobin (HbA1c) 8%, C peptide <0.3 ng/mL, sodium 131 mmol/L, chloride 93 mmol/L, potassium 5.2 mmol/L, and calculated serum osmolality 385 mOsm/kg. The presumptive diagnosis on admission was nonketotic hyperosmolar syndrome precipitated by urinary infection. This is the first case report of hyperosmolar coma in a patient with type 1 diabetes with chronic kidney disease.
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PMID:Nonketotic hyperosmolar coma in a patient with type 1 diabetes-related diabetic nephropathy: case report. 1641 50

This chapter describes a physiological and profound effect of amylin to inhibit meal-related glucagon secretion. Glucagon is processed from a large precursor, proglucagon, in a tissue-specific manner in pancreatic alpha-cells. In addition to amino acid nutrient stimuli, glucagon is also secreted in response to stressful stimuli, such as hypoglycemia and hypovolemia. Glucagon primarily acts on liver to initiate glycogenolysis and gluconeogenesis, resulting in a rapid increase in endogenous production of glucose. With longer stimulation, glucagon action at the liver results in a glucose-sparing activation of free fatty acid oxidation and production of ketones. During hypoglycemia, glucagon secretion is clearly a protective feed-back, defending the organism against damaging effects of low glucose in brain and nerves (neuroglycopenia). Amino acid-stimulated glucagon secretion during meals has a different purpose: amino acids stimulate insulin secretion, which mobilizes amino acid transporters and effects their storage in peripheral tissues. At the same time, insulin obligatorily recruits GLUT4 glucose transporters in muscle and fat. The hypoglycemic potential of such GLUT4 mobilization is averted only by the simultaneous liberation of endogenous glucose in response to feedforward (anticipatory) glucagon secretion. The effect of amylin and its agonists to inhibit amino acid-stimulated glucagon secretion is both potent (EC50 = 18 pM) and profound (approximately 70% inhibition). This glucagonostatic action appears to be extrinsic to the pancreatic islet, occurring in intact animals and in patients, but not in isolated islets or isolated perfused pancreas preparations. On the other hand, the effect of hypoglycemia to stimulate glucagon secretion, which is intrinsic to the islet and occurs in isolated preparations, is not affected by amylin or its agonists. The physiological interpretation of these actions fits with the general concept, illustrated in Fig. 1, that amylin and insulin secreted in response to meals shut down endogenous production as a source of glucose, in favor of that derived from the meal. Amylin and insulin secreted in response to nutrients already absorbed act as a feedback switch for glucose sourcing. The insulinotropic (incretin) gut peptides, GLP-1 and GIP, secreted in response to yet-to-be-absorbed intraluminal nutrients, amplify beta-cell secretion and thereby activate the glucose sourcing switch in a feedforward manner. Hypoglycemia-stimulated glucagon secretion and nutrient (amino acid)-stimulated glucagon secretion are two clearly different processes, differently affected by amylin. The balance of glucose fluxes is disturbed in diabetic states, partly as a result of inappropriate glucagon secretion. Although glucose production due to glucagon secreted in response to hypoglycemia is normal or even reduced in diabetic patients, the secretion of glucagon (and production of endogenous glucose) in response to protein meals is typically exaggerated. Absence of appropriate beta-cell suppression of alpha-cell secretion has been invoked as a mechanism that explains exaggerated glucagon responses, especially prevalent in patients with deficient beta-cell secretion (type 1 diabetes and insulinopenic type 2 diabetes). A proposed benefit of insulin replacement therapy is the reduction of absolute or relative hyperglucagonemia. High glucagon is said to be necessary for ketosis in severe forms of diabetes. A further benefit of reversing hyperglucagonemia is reduction of the excessive endogenous glucose production that contributes to fasting and postprandial hyperglycemia in diabetes. The idea that amylin is a part of the beta-cell drive that normally limits glucagon secretion after meals fits with the observation that glucagon secretion is exaggerated in amylin-deficient states (diabetes characterized by beta-cell failure). This proposal is further supported by the observation that postprandial glucagon suppression is restored following amylin replacement therapy in such states. These observations argue for a therapeutic case for amylin replacement in patients in whom excess glucagon action contributes to fasting and postprandial hyperglycemia and ketosis. The selectivity of amylin's glucagonostatic effect (wherein it is restricted to meal-related glucagon secretion, while preserving glucagon secretion and glucagon action during hypoglycemia) may confer additional benefits; the patient population amenable to amylin replacement therapy is likely to also be receiving insulin replacement therapy, and is thereby susceptible to insulin-induced hypoglycemia. Most explorations of the biology of amylin have used the endogenous hormone in the cognate species (typically rat amylin in rat studies). Clinical studies have typically employed the amylinomimetic agent pramlintide. Studies of amylinomimetic effects on glucagon secretion include effects of rat amylin in anesthetized non-diabetic rats (Jodka et al., 2000; Parkes et al., 1999; Young et al., 1995), effects of rat amylin in isolated perfused rat pancreas (Silvestre et al., 1999), effects of pramlintide in anesthetized non-diabetic rats (Gedulin et al., 1997b,c,d, 1998), effects of pramlintide in patients with type l diabetes (Fineman et al., 1997a,b,c,d, 1998a; Holst, 1997; Nyholm et al., 1996, 1997a,b,c; Orskov et al., 1999; Thompson and Kolterman, 1997), and effects in patients with type 2 diabetes (Fineman et al., 1998b). In addition, effects of amylin antagonists have been observed in isolated preparations (Silvestre et al., 1996), and effects of antagonists or neutralizing antibody have been determined in whole-animal preparations (Gedulin et al., 1997a,e,f).
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PMID:Inhibition of glucagon secretion. 1649 45

The long-term complications of diabetes are the leading causes of morbidity and mortality in the type 1 diabetic population and remain a major public health issue. Hyperglycemia is one of the major risk factors in the development of vascular complications. A growing body of evidence indicates that hyperglycemia leads to increased oxidative stress and monocyte and endothelial cell dysfunction. In addition to hyperglycemia, type 1 diabetic patients frequently experience ketosis (hyperketonemia). The blood concentration of ketone bodies reaches higher than 25mM in diabetics with severe ketosis. Traditionally, clinical practice has considered hypertketonemia to be present only in type 1 diabetic patients. Newer data indicate that diabetic ketoaciosis or hyperketonemia co-exists with hyperglycemia among older type 2 diabetic patients and in African Americans and other minority groups with type 2 diabetes. This review will focus on the role of hyperketonemia in the etiology of oxidative stress in diabetic patients. The data presented here illustrate that the ketone body acetoacetate (AA) can generate superoxide radicals and cause increases in oxidative stress and cellular dysfunction. The data included in this review demonstrate that blood levels of markers of oxidative stress are elevated in hyperketonemic patients compared with those of normoketonemic diabetic patients. Thus, both in vitro and in vivo research indicate that ketosis can generate oxygen radicals and result in excess cellular oxidative stress in type 1 diabetic patients. Elevated oxidative stress levels in ketotic patients can play a significant role in the development of vascular inflammation and contribute to the increased incidence of vascular disease and complications associated with type 1 diabetes.
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PMID:Hyperketonemia (ketosis), oxidative stress and type 1 diabetes. 1678 14

Differentiation of the various forms of diabetes is necessary for therapeutic reasons. Typical signs of type 2 diabetes are age over 40, obesity, and other markers for metabolic syndrome, a positive famitory, gradual development of the classical symptoms, and no evidence of ketosis. It is important to distinguish this from LADA (latent autoimmune diabetes of adulthood), a form of type 1 diabetes mellitus. To establish this differential diagnosis antibody testing is employed. Antibody tests in patients with newly manifest diabetes make good sense when the clinical diagnosis is not unequivocal, that is, to distinguish it from type 2 diabetes, MODY diabetes, hereditary and secondary forms. At present, immunodiagnosis is used too often in unambiguous cases of type 1 diabetes, but too rarely in supposed type 2 diabetes. As a rule, LADA patients are GADA-positive. If MODY diabetes is suspected, a genetic examination is indicated. In patients with GDM, antibody testing with GADA makes sense, in particular in slim patients receiving insulin treatment, since these patients have a high risk for developing a postpartum diabetes already in the first years.
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PMID:[Diabetes mellitus--differential diagnosis]. 1680 91

Hospitalization for diabetic ketoacidosis (DKA) is increasing, perhaps due to the rising incidence of DKA in patients with type 2 diabetes mellitus (T2DM). Ethnic minority groups are at increased risk for T2DM. This study aimed at elucidating the characteristics of patients with ketosis-prone diabetes in a predominantly ethnic minority population. We performed a retrospective analysis of adults admitted with DKA at the Bronx Lebanon Hospital Center, Bronx, NY over 3 years. The patients were divided into cohorts based on type of diabetes and ethnicity. The cohorts were described and compared using statistical methods. We recorded 219 cases of DKA in 168 patients, 97% of whom were African American or Hispanic. Fifty-three (32%) patients had T2DM. New-onset diabetes, which was more common in T2DM (P < .0001), and African Americans (P = .008), occurred in 42 patients (25%). Readmission with DKA was more common in the Hispanic patients with type 1 diabetes mellitus (T1DM) (P = .0001). Type 2 diabetes mellitus was more prevalent in the African Americans (P = .04). Patients with T1DM had more severe acidosis than patients with T2DM (lower pH and bicarbonate and larger anion gap; P = .03, .02, and .005, respectively). Creatinine level was higher in patients with T2DM (P = .04) who were also less likely to have identifiable precipitating causes (P = .02). Hemoglobin A(1c) level was higher in patients with new-onset diabetes (P < .05), but did not differ between those with T1DM and T2DM. Mortality, which was 2%, occurred only in the African Americans with T2DM. We conclude that DKA is an important mode of initial presentation of T2DM, with new-onset T2DM accounting for about 60% of all new cases of DKA. African American patients with T2DM, in comparison with the Hispanic patients, are more susceptible to developing DKA. Diabetic ketoacidosis could occur in T2DM without any identifiable precipitant. The rising incidence of DKA may be attributable to its increasing occurrence in T2DM; therefore, measures aimed at primary prevention of T2DM are worthwhile.
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PMID:Admissions for diabetic ketoacidosis in ethnic minority groups in a city hospital. 1722 29

Patients with type 1 diabetes and poor metabolic control can develop hepatomegaly due to intrahepatic glycogen deposition. If these patients also have elevated liver enzymes, dyslipidemia, cushingoid features and delayed growth or sexual maturation, Mauriac syndrome can be diagnosed. This disorder is common and reversible with optimization of insulin therapy. We report three adolescents with type 1 diabetes and a long-standing history of poor glycemic control, who developed hepatomegaly, elevated liver enzymes and dyslipidemia with preserved liver function. One of these patients also had delayed growth and another had hypogonadotropic hypogonadism. Liver ultrasound showed changes suggestive of glycogenosis. In all three patients, optimization of insulin therapy achieved good glycemic control and reversed the manifestations within 2 weeks. The etiology of Mauriac syndrome is controversial since both prolonged hyperglycemia and hyperinsulinization produce glycogen accumulation in the liver. Hypercortisolism (due to ketosis or hypoglycemia) contributes to glycogen storage and also causes growth and sexual maturation delay.
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PMID:[Hepatomegaly due to glycogen storage disease and type 1 diabetes mellitus]. 1769 62

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