Strong Family History Of Type Research Articles

THU370 A Case Of Ketosis-prone Diabetes In A Caucasian Man

Abstract Disclosure: Z. Saeed: None. C. Labib: None. M. Trabulsi: None. M. Varatharajah: None. Introduction: Ketosis-prone diabetes (KPD) also known as Flatbush diabetes, atypical diabetes and type 1.5 diabetes was first reported in the 1990s in African Americans in the Flatbush neighborhood of Brooklyn, New York. Its exact incidence is still unknown; however, it predominantly affects African American and Hispanic population and is less prevalent in Asians and Caucasians. It presents as diabetic ketoacidosis, a hyperglycemic emergency, in patients with no prior history of diabetes. In addition, it is usually seen in middle-aged, obese patients with a strong family history of Type 2 diabetes mellitus. Here we briefly describe the case of a lean 62-year-old man who presented to the hospital with HHS/DKA and was diagnosed with ketosis-prone diabetes. Case Presentation: 62-year-old man (BMI 21.37 Index) with a past medical history of alcoholic cirrhosis, Crohn’s disease and no personal or family history of diabetes presented to the hospital with complaint of nausea, polyuria and polydipsia. He was found to have hyperosmolar hyperglycemic state with diabetic ketoacidosis. He had a blood glucose of 833 mg/dL (70-110 mg/dL), anion gap of 14, sodium 111 mmol/L (136-145 mmol/L), potassium 7.0 mmol/L (3.5-5.1 mmol/L), creatinine 5.7mg/dL (0.6-1.3 mg/dL), pH 7.26 L (7.35-7.45 pH units), bicarbonate 16 mmol/L (22-34 mmol/L). He was started on an Insulin drip and later transitioned to subcutaneous long and short acting insulin after closure of anion gap. His Hemoglobin A1c was found to be 12.8% (4.8-6.1% A1C, Cpeptide 4.32 ng/mL (0.48-5.05 ng/mL), GAD65 antibody was negative. Four months prior to his hospital admission, his Hemoglobin A1C was 4.9%. Patient was discharged from the hospital on Insulin NPH/Regular 70/30 twice a day and sliding scale with meals. He was followed outpatient in clinic. Within a month of discharge he began to have episodes of symptomatic hypoglycemia, lowest recorded blood sugar was 49. His Insulin NPH/Regular was gradually tapered; he did not require the sliding scale at all. Four months after the episode of HHS/DKA, his repeat hemoglobin A1C was 5.7%. Case Discussion: Despite being known for around three decades now, the exact mechanism of ketosis prone diabetes is still poorly understood. It is thought to be due to insulin resistance as well as severe deficits in insulin secretion. It is classified further based on beta cell function and autoimmunity. In patients with preserved beta cell function and absence of autoimmunity, like our patient, with aggressive management insulin can eventually be discontinued. However, these patients remain at risk of developing diabetes later in life. Our case aims to shed light on the ubiquity of this disease so that physicians can diagnose it promptly and treat accordingly. Presentation: Thursday, June 15, 2023

Microalbuminuria in Women with Risk Factors for Gestational Diabetes Mellitus in Some Selected Hospitals in Sokoto, Nigeria

Gestational diabetes mellitus (GDM) is a common metabolic abnormality which affects approximately 2-5% of pregnancies. Risk factors such as previous infants with macrosomia, strong family history of type 2 diabetes or GDM, poor glycaemic control and high pre-pregnancy body mass index (BMI) have been implicated in the development of GDM. This study was conducted to determine the prevalence of Microalbumnuria in women with risk factors for GDM and to estimate the levels of Urinary Microalbumin in these women. Fifty (50) pregnant women with risk factors for GDM and 50 controls (pregnant women without risk factors for GDM) were evaluated for Microalbuminuria. Microalbuminuria was estimated using Turbidimetric method, Random Plasma Glucose was estimated using Glucose oxidase method, serum Urea was estimated using Diacetyl Monoxime method, Creatinine was estimated using Jaffe Slot method and Albumin was estimated using Bromo Cresol Green method. The prevalence of Microalbuminuria in women with risk factors for GDM was 22%. Urinary microalbumin was significantly higher in the study subjects (56.36 ± 8.44 mg/L) than in the control (17.32 ± 4.5) mg/L. The mean ± standard error of mean of random plasma glucose in the study subjects was (5.84 ± 0.16) mmol/L and that of the control was (4.33 ± 0.14) mmol/L. The mean ± standard error of mean Serum Urea, Creatinine and Albumin were (4.1 ± 0.15) mmol/L, (0.70 ± 0.03) mg/dL, and (3.06 ± 0.05) g/dL respectively while that of the control was (3.47 ± 0.13) mmol/L, (0.63 ± 0.01) mg/dL and (2.78 ± 0.09) g/dL respectively. Obesity was strongly correlated to microalbuminuria.

Risperidone-induced type 2 diabetes presenting with diabetic ketoacidosis.

SummaryA 28-year-old male presented with 2 days of vomiting and abdominal pain, preceded by 2 weeks of thirst, polyuria and polydipsia. He had recently started risperidone for obsessive-compulsive disorder. He reported a high dietary sugar intake and had a strong family history of type 2 diabetes mellitus (T2DM). On admission, he was tachycardic, tachypnoeic and drowsy with a Glasgow Coma Scale (GCS) of 10/15. We noted axillary acanthosis nigricans and obesity (BMI 33.2 kg/m2). Dipstick urinalysis showed ketonuria and glycosuria. Blood results were consistent with diabetic ketoacidosis (DKA), with hyperosmolar state. We initiated our DKA protocol, with intravenous insulin, fluids and potassium, and we discontinued risperidone. His obesity, family history of T2DM, acanthosis nigricans and hyperosmolar state prompted consideration of T2DM presenting with ‘ketosis-prone diabetes’ (KPD) rather than T1DM. Antibody markers of beta-cell autoimmunity were subsequently negative. Four weeks later, he had modified his diet and lost weight, and his metabolic parameters had normalised. We reduced his total daily insulin dose from 35 to 18 units and introduced metformin. We stopped insulin completely by week 7. At 6 months, his glucometer readings and glycated haemoglobin (HbA1c) level had normalised.Learning points:Risperidone-induced diabetic ketoacidosis (DKA) is not synonymous with type 1 diabetes, even in young white patients and may be a manifestation of ‘ketosis-prone’ type 2 diabetes (KPD).KPD is often only confirmed after the initial presentation, when islet autoimmunity and cautious phasing out of insulin therapy have been assessed, and emergency DKA management remains the same.As in other cases of KPD, a family history of T2DM and presence of cutaneous markers of insulin resistance were important clinical features suggestive of an alternative aetiology for DKA.

Diabetic ketoacidosis: a challenging diabetes phenotype.

SummaryWe describe three patients presenting with diabetic ketoacidosis secondary to ketosis prone type 2, rather than type 1 diabetes. All patients were treated according to a standard DKA protocol, but were subsequently able to come off insulin therapy while maintaining good glycaemic control. Ketosis-prone type 2 diabetes (KPD) presenting with DKA has not been described previously in Irish patients. The absence of islet autoimmunity and evidence of endogenous beta cell function after resolution of DKA are well-established markers of KPD, but are not readily available in the acute setting. Although not emphasised in any current guidelines, we have found that a strong family history of type 2 diabetes and the presence of cutaneous markers of insulin resistance are strongly suggestive of KPD. These could be emphasised in future clinical practice guidelines.Learning points:Even in white patients, DKA is not synonymous with type 1 diabetes and autoimmune beta cell failure. KPD needs to be considered in all patients presenting with DKA, even though it will not influence their initial treatment.Aside from markers of endogenous beta cell function and islet autoimmunity, which in any case are unlikely to be immediately available to clinicians, consideration of family history of type 2 diabetes and cutaneous markers of insulin resistance might help to identify those with KPD and are more readily apparent in the acute setting, though not emphasised in guidelines.Consideration of KPD should never alter the management of the acute severe metabolic derangement of DKA, and phasing out of insulin therapy requires frequent attendance and meticulous and cautious surveillance by a team of experienced diabetes care providers.

A novel HNF4A mutation in the antenatal clinic

A 35-year-old woman with type 1 diabetes attended the antenatal diabetes clinic at the John Radcliffe Hospital, Oxford, early in the pregnancy of her second child. She had had type 1 diabetes since the age of 13 on the background of a strong family history of type 1 diabetes in her mother, uncle and cousin. She had a normal range BMI pre-pregnancy. Her first pregnancy had been successful with the birth of a son at 37 weeks gestation, weighing 3.5 kg. It was noted in the current pregnancy that she had very tight glycaemic control and that her HbA1c had fallen from 5.9% to 5.3%, using relatively small total daily doses of insulin (Lantus 2 units per day, Novorapid 2–4 units tds), with a tendency towards hypoglycaemia. Given her clinical picture and family history, a query was raised as to her underlying diabetes type. Her GAD and ICA pancreatic auto-antibodies were checked and found to be negative, and her C-peptide level was very low at 277pmol/L, with a concurrent glucose level of 5.0 mmol/L. Monogenic diabetes had already been considered and tested for back in 1999 by the paediatric team. Results from the Department of Molecular Genetics at the Royal Devon & Exeter Hospital stated that she was negative for an HNF1A gene mutation. However, other MODY subtypes had not been tested for and so targeted next-generation sequencing of the known MODY genes on the family's saved samples was requested. No known pathogenic mutation was identified, but a novel heterozy-gous missense variant (p.Thr211Asn, NM_175914.4:c.632C > A) in the HNF4A gene was found. The patient's mother, who was diagnosed with presumed type 1 diabetes at the age of 15, was also heterozygous for the variant. The patient was certainly atypical for type 1 diabetes and the presence of the mutation in the mother would suggest that the mutation is likely to be pathogenic (although there was a 50% chance of the mother having the variant regardless). Despite good glycaemic control, the baby's abdominal circumference was greater than the 97th centile for growth on the 28-week scan. Subsequent growth is demonstrated in Figure 1. At 34 weeks, the patient developed an antepartum haemorrhage, was admitted for IV steroids (to aid fetal lung maturation), and underwent delivery by caesarean section shortly afterwards. The baby's weight was 3.8 kg, which is greater than the 99th centile for this gestational age. Ultimately, it would seem likely that this genetic variant had implications in this pregnancy. HNF4A plays a key role in determining fetal birthweight and mutations result in an increase in birthweight by an average of 800 g.1 Ten percent of HNF4A MODY patients also have transient neonatal hypoglycaemia, although this was not found in this case. Fetal growth increasing above the 75th centile, in spite of good glycaemic control in the mother, is also indicative of good evidence for pathogenicity. As with all forms of diabetes, in a variety of settings, it is important to be increasingly aware of the many different types of monogenic diabetes and their associated complications.2-4 Acknowledgements and references are available in Practical Diabetes online at www.practicaldiabetes.com. Many thanks to: Dr Rustam Rea, Prof Katherine Owen, Dr Lucy MacKillop, Dr Alistair Lumb, Dr Jonathan Levy, Sister Katy Bartlett, Miss Deborah Harrington and Miss Veronica Miller of Oxford University Hospitals Foundation Trust, and Kevin Colclough, Clinical Scientist, Royal Devon & Exeter Foundation Trust.

An interesting case of new-onset ketosis-prone diabetes in a Scottish teaching hospital

Background: Clinical teaching for many years has been to assume that diabetic ketoacidosis is pathognomic of type 1 diabetes. However, this dogma is now increasingly questioned as increasing numbers of people are admitted with diabetic ketoacidosis without the typical features of autoimmune type 1 diabetes. Such individuals are increasingly diagnosed with ketosis-prone diabetes, a heterogenous syndrome where individuals present with diabetic ketoacidosis or unprovoked ketosis but are usually autoantibody negative and have no residual β-cell function. Classification of ketosis-prone diabetes using the Aβ system can aid in diagnosis and treatment decisions. Case report: An Afro-Caribbean male presented with hyperglycaemic ketosis. Initially diagnosed with type 1 diabetes and treated with a basal-bolus regimen, he was able to stop insulin completely within one month of presentation following rapid improvements in glycaemic control and repeated hypoglycaemia. Clinical investigation revealed he was negative for β-cell autoantibodies and had a stimulated C-peptide of >0.5 pmol/ml, suggesting preserved β-cell function. A diagnosis of ketosis-prone diabetes (A-β+) was made. Discussion: A high index of suspicion for ketosis-prone diabetes should arise when someone presents with diabetic ketoacidosis, who is obese, middle-aged, male and with a strong family history of type 2 diabetes and from a Black or Hispanic population. There is currently limited evidence on the pathophysiology of this transient β-cell defect, with suggestions that it may be related to glucotoxicity.

Early metabolic defects in Arab subjects with strong family history of Type 2 diabetes.

It is widely accepted that the genetic make-up of the subject plays a pivotal role in the development of insulin resistance and β cell failure. The objective of this study was to examine whether the same or distinct genetic backgrounds contribute to the development of insulin resistance and β cell failure. We examined insulin sensitivity and β cell function in lean normal glucose tolerance subjects from 3 multigeneration Arab families. Families 1 and 2 had strong history of Type 2 diabetes (T2DM), while no member of family 3 had T2DM. Subjects in family 1 manifested increased basal plasma free fatty acid (FFA) concentration and impaired suppression of plasma FFA during the OGTT compared to subjects in family 3. Subjects in family 2 had comparable fasting plasma FFA and suppression of plasma FFA during the OGTT to family 3. Both the absolute plasma glucose concentrations, and incremental area under the plasma glucose curve (ΔG0-120) during the OGTT were comparable in subjects of families 1 and 2, and were decreased in subjects of family 3. Whole body and muscle insulin sensitivity were comparable in subjects from families 2 and 3, and both were significantly decreased in subjects of family 1. Beta cell function was comparable in subjects of families 1 and 3 and was significantly decreased in subjects of family 2. These results demonstrate that distinct genetic background contributes to the development of insulin resistance and β cell dysfunction in Arab individuals.

English

Abstract- The pandemic of metabolic disorders is accelerating in the urbanized world posing huge burden to health and economy. The key pioneer to most of the metabolic disorders is insulin dependent diabetes mellitus or Type 1 Diabetes Mellitus (T1DM) and non-insulin dependent diabetes mellitus commonly known as Type 2 Diabetes Mellitus (T2DM). Both of these forms of diabetes are polygenic and multifactorial. A newly discovered form of diabetes is Maturity Onset Diabetes of the young (MODY). MODY is a monogenic form of diabetes and it is inherited as autosomal dominant disorder. Its age of onsets is at 14-25 years in individuals who have a strong family history of Type 2 Diabetes Mellitus (T2DM). In most of the MODY patients genes involved in mediating and controlling the expression of insulin are concerned. Till date eleven genes that cause MODY have been identified all over the world. But in Pakistan no genetic research has been done on MODY. The aims of the present study were to examine the prevalence and nature of mutation in three common MODY genes on the basis of their occurrence in European populations. These three MODY genes are HNF4-Alpha, GCK, and HNF1-Alpha. 22 members spanning four generations and 11 affected with MODY in Pakistani population were examined. To determine the linkage or exclusion study of the family to six known loci for MODY, a minimum of two micro satellite markers each of the candidate regions of these loci for MODY were genotyped in all the available individuals of this family. To identify genes involved in susceptibility to MODY and to discover new genes and mutations contributing to MODY in Pakistani population, Single Strand Conformation Polymorphism technique (SSCP) was used. Our findings highlighted that those unidentified MODY genes that facilitate to cause this form of diabetes in European population may play a central role for diabetes characterized by autosomal dominant transmission in Pakistani population.

Gestational Diabetes Clinic in the Public Health Setting

Gestational diabetes mellitus (GDM), or “carbohydrate intolerance of variable severity with onset or first recognition during pregnancy,” results from insulin resistance and relative insulin deficiency, usually in the second trimester.1 This condition affects between 4 and 9% of all pregnancies.2 With GDM, there are increased fetal complications of macrosomia, shoulder dystocia, and neonatal hyperglycemia, as well as maternal risks of preeclampsia and polyhydramnois.3,4 Also, it has been shown that 33% of GDM patients require Cesarean section compared to 20% of pregnant patients without GDM.5 Women who are of Hispanic or Asian descent are at the highest risk of developing GDM.6 According to the American Diabetes Association (ADA),7 assessment for undiagnosed type 2 diabetes should be completed at the first prenatal visit. Patients who are high risk (those with severe obesity, a history of GDM, a diagnosis of polycystic ovarian syndrome, a strong family history of type 2 diabetes, or glycosuria) should be screened using standard diagnostic testing. Diagnosis is based on the following results: A1C ≥ 6.5%, fasting plasma glucose level ≥ 126 mg/dl, 2-hour plasma glucose level ≥ 200 mg/dl during an oral glucose tolerance test (OGTT), or classic symptoms of hyperglycemia with a random blood glucose level ≥ 200 mg/dl.7 All remaining pregnant women who are not known to have diabetes should have testing for GDM at 24–28 weeks of gestation using a 75-g, 2-hour OGTT. Patients are diagnosed with GDM if they have any of the following plasma glucose values: fasting ≥ 92 mg/dl, 1-hour ≥ 180 mg/dl, or 2-hour ≥ 153 mg/dl.7 Upon diagnosis of GDM, medical nutrition therapy, self-monitoring of blood glucose (SMBG), and fetal monitoring are initiated. A study by Landon et al.8 found that treatment of mild GDM resulted in a lower …

South Asian version of flatbush diabetes mellitus- A case report and review article

Ketosis prone type 2 diabetes mellitus which was once described as “atypical diabetes” is being recognized increasingly worldwide; being originally described in African population has been seen in multiple ethnic groups, especially in urban areas. These patients are typically obese, middle-aged men with a strong family history of type 2 diabetes. The pathophysiologic mechanisms involved in its cause are unknown, but preliminary evidence suggests that patients with ketosis-prone type 2 diabetes have a unique propensity to glucose desensitization. These individuals have negative autoantibodies associated with type 1 diabetes but frequently HLA class II DRB1*03 and/or DRB1*04 are detected. Severe impairment of both insulin secretion and insulin action are found at presentation. Aggressive diabetes management results in marked improvement in beta cell function and insulin sensitivity sufficient to allow discontinuation of insulin therapy within a few months of treatment. In the long run, insulin can be substituted with oral hypoglycemic agents in most of these patients under careful supervision and close follow up. Molecular investigations into KPD syndromes utilizing multiple approaches (genomic, metabolic, proteomic) to generate etiological hypotheses can help us understand the underlying defects of insulin secretion and sensitivity in these and other types of diabetic patients. Key words: Diabetesis mellitus (DM), ketosis prone diabetes (KPD), diabetic ketoacidosis (DKA), latent auto-immune diabetes of adults (LADA).

A−β− Subtype of Ketosis-Prone Diabetes Is Not Predominantly a Monogenic Diabetic Syndrome

OBJECTIVEKetosis-prone diabetes (KPD) is an emerging syndrome that encompasses several distinct phenotypic subgroups that share a predisposition to diabetic ketoacidosis. We investigated whether the A−β− subgroup of KPD, characterized by complete insulin dependence, absent β-cell functional reserve, lack of islet cell autoantibodies, and strong family history of type 2 diabetes, represents a monogenic form of diabetes.RESEARCH DESIGN AND METHODSOver 8 years, 37 patients with an A−β− phenotype were identified in our longitudinally followed cohort of KPD patients. Seven genes, including hepatocyte nuclear factor 4A (HNF4A), glucokinase (GCK), HNF1A, pancreas duodenal homeobox 1 (PDX1), HNF1B, neurogenic differentiation 1 (NEUROD1), and PAX4, were directly sequenced in all patients. Selected gene regions were also sequenced in healthy, unrelated ethnically matched control subjects, consisting of 84 African American, 96 Caucasian, and 95 Hispanic subjects.RESULTSThe majority (70%) of the A−β− KPD patients had no significant causal polymorphisms in either the proximal promoter or coding regions of the seven genes. The combination of six potentially significant low-frequency, heterozygous sequence variants in HNF-1α (A174V or G574S), PDX1 (putative 5′–untranslated region CCAAT box, P33T, or P239Q), or PAX4 (R133W) were found in 27% (10/37) of patients, with one additional patient revealing two variants, PDX1 P33T and PAX4 R133W. The A174V variant has not been previously reported.CONCLUSIONSDespite its well-circumscribed, robust, and distinctive phenotype of severe, nonautoimmune-mediated β-cell dysfunction, A−β− KPD is most likely not a predominantly monogenic diabetic syndrome. Several A−β− KPD patients have low-frequency variants in HNF1A, PDX1, or PAX4 genes, which may be of functional significance in their pathophysiology.

Chronic Low‐Dose Lipid Infusion in Healthy Patients Induces Markers of Endothelial Activation Independent of Its Metabolic Effects

Elevated plasma triglyceride/free fatty acid (FFA) levels and insulin resistance may promote atherosclerosis through endothelial activation (ie, increased expression of intercellular adhesion molecule 1 [ICAM-1]/vascular adhesion molecule 1 [VCAM-1], and endothelin-1 [ET-1]) in patients with the metabolic syndrome, but this has never been directly tested. The authors measured endothelial activation and insulin sensitivity (euglycemic insulin clamp with [3-(3)H]-glucose) after a 4-day low-dose lipid infusion that elevated plasma FFA to levels observed in the metabolic syndrome in 20 lean, non-diabetic insulin-resistant subjects with a strong family history of type 2 diabetes mellitus (FH(+)) and 10 insulin-sensitive volunteers without a family history of type 2 diabetes mellitus (FH(-)). Low-dose lipid infusion reduced insulin sensitivity by approximately 25% in insulin-sensitive FH(-)controls but did not worsen preexisting insulin resistance in FH(+). Low-dose lipid infusion elevated plasma ICAM and VCAM levels similarly in both groups (approximately 12%-18%; P<.01 vs baseline), while plasma ET-1 levels increased more in FH(+)vs FH(-)(46% vs 10%; P=.005). Increased plasma FFA levels closely correlated with elevated ICAM (r=0.60; P<.01), VCAM, and ET-1 levels (r=0.39 and r=0.42, respectively; P<.05). Low-dose lipid infusion induces endothelial activation in both lean insulin-resistant (FH(+)) and insulin-sensitive (FH(-)) healthy patients, regardless of changes in insulin sensitivity. These results prove that even a modest lipid oversupply may be sufficient to trigger a deleterious endothelial response.

Abnormal postprandial PYY response in insulin sensitive nondiabetic subjects with a strong family history of type 2 diabetes

Gut-derived hormone peptide YY (PYY) is low in subjects with obesity and type 2 diabetes (T2D). However, it is unknown whether this is a primary defect or a consequence of metabolic disturbances. In this study, we aimed to assess whether low fasting and postprandial PYY secretion is an early defect, potentially promoting the development of obesity and T2D, and whether it is modified by macronutrient content. Prospective cross-sectional cohort study. Nine individuals with a strong family history of T2D (REL) and seven age and adiposity matched individuals with no family history of T2D (CON). Metabolic studies including hyperinsulinemic-euglycemic clamp, dual X-ray absorptiometry and two meal tests containing 1000 kcal with an either high fat (76%) or high carbohydrate (76%) content. Fasting and postprandial PYY levels were measured and analyzed for potential correlations with markers for adiposity and insulin resistance. Insulin sensitivity was not different between REL and CON. Fasting glucose, insulin, triglycerides and PYY were also not different between groups. However, the postprandial incremental area under curve (AUC) of PYY was significantly lower in REL after the high carbohydrate (HCHO) meal (+27.3 vs +60.6% increase from baseline, P=0.038). The AUC of insulin during HCHO meal correlated negatively with both AUC and fasting level of PYY (r=-0.58 and -0.60, respectively, P<0.05). A blunted postprandial PYY secretion is observed in a very early stage in the development of T2D in genetically susceptible individuals. This defect precedes the presence of insulin resistance and adiposity, and could therefore predispose to the development of T2D.

Impaired Fat Oxidation After a Single High-Fat Meal in Insulin-Sensitive Nondiabetic Individuals With a Family History of Type 2 Diabetes

Individuals with insulin resistance and type 2 diabetes have an impaired ability to switch appropriately between carbohydrate and fatty acid oxidation. However, whether this is a cause or consequence of insulin resistance is unclear, and the mechanism(s) involved in this response is not completely elucidated. Whole-body fat oxidation and transcriptional regulation of genes involved in lipid metabolism in skeletal muscle were measured after a prolonged fast and after consumption of either high-fat (76%) or high-carbohydrate (76%) meals in individuals with no family history of type 2 diabetes (control, n = 8) and in age- and fatness-matched individuals with a strong family history of type 2 diabetes (n = 9). Vastus lateralis muscle biopsies were performed before and 3 h after each meal. Insulin sensitivity and fasting measures of fat oxidation were not different between groups. However, subjects with a family history of type 2 diabetes had an impaired ability to increase fatty acid oxidation in response to the high-fat meal (P < 0.05). This was related to impaired activation of genes involved in lipid metabolism, including those for peroxisome proliferator-activated receptor coactivator-1alpha (PGC1alpha) and fatty acid translocase (FAT)/CD36 (P < 0.05). Of interest, adiponectin receptor-1 expression decreased 23% after the high-fat meal in both groups, but it was not changed after the high-carbohydrate meal. In conclusion, an impaired ability to increase fatty acid oxidation precedes the development of insulin resistance in genetically susceptible individuals. PGC1alpha and FAT/CD36 are likely candidates in mediating this response.

Case Study: A 30-Year-Old Man With Metformin-Treated Newly Diagnosed Diabetes and Abdominal Pain

M.P. is a 30-year-old man who was diagnosed with type 2 diabetes 2 weeks before admission to the hospital. He has a strong family history of type 2 diabetes. He smokes heavily (> 20 cigarettes/day) and admits to some alcohol consumption. His primary care physician had started him on metformin, 500 mg three times daily. There were no complications of diabetes at the time of presentation. Two days before his admission, he developed generalized abdominal discomfort, watery diarrhea, and bilious vomiting. He denied any history suggestive of food poisoning or recent surgery. He was apyrexial on admission. His blood pressure was 170/101 mmHg, pulse was 100 bpm, and temperature was 98.9°F. There were no signs suggestive of peritonitis, and his abdomen was soft without guarding. He had deep-seated tenderness in the epigastric region. Initial investigations showed a white blood count of 25.9 × 109, hemoglobin of 15.8 g/dl, and C-reactive protein (CRP) of 200 mg. Renal functions were normal, and liver function tests were normal except for an increased lactic acid dehydrogenase (LDH) level of 848 IU/l. Figure 1. Chest X-ray showing air under diaphragm (arrows). His metformin was stopped because his gastrointestinal symptoms were …

Reduced NO synthesis and eNOS mRNA expression in endothelial cells from newborns with a strong family history of type 2 diabetes

A deficient synthesis of nitric oxide (NO) may play a role in the early endothelial dysfunction of healthy humans with a strong family history of type 2 diabetes (DM2). In this study, we evaluate the intracellular synthesis of NO and the expression of eNOS transcripts in human umbilical vein endothelial cells (HUVECs), exposed to high glucose concentrations, of healthy newborns with (experimental) and without (control) a strong family history of DM2. HUVECs were incubated in M-199 culture media (containing a 5 mmol/L physiological glucose concentration) or supraphysiological glucose concentrations (15 or 30 mmol/L), for 48 h. Flow cytometry, reactive of Griess and RT-PCR were used to determine intracellular NO synthesis, presence of NO metabolites, and expression of eNOS, GLUT1 or p53 transcripts. NO synthesis in experimental HUVECs showed a progressive reduction in the presence of increasing glucose concentration (11% for 5 mmol to 8% for 30 mmol; p < 0.01), whereas control HUVECs showed an increase in NO synthesis (3% for 5 mmol to 31% for 30 mmol; p < 0.001). In experimental HUVECs, we found a diminished expression of eNOS and p53, and also an enhanced expression of GLUT1 mRNA transcripts. Control HUVECs showed an increase in eNOS, and no modifications in p53 or GLUT1 mRNA transcripts. Our results show how HUVECs, isolated from healthy newborns with a strong family history of DM2, have an abnormal intracellular synthesis of NO and an impaired expression of eNOS, GLUT1 and p53 genes, all associated with NO synthesis.

Acute hyperglycemic emergencies in children with type 2 diabetes

Acute hyperglycemic emergencies in children with type 2 diabetes

HUVECs from newborns with a strong family history of diabetes show diminished ROS synthesis in the presence of high glucose concentrations

A family history of type 2 diabetes mellitus (DM) increases the probability to develop DM and endothelial dysfunction. The probable mechanism involves augmented reactive oxygen species (ROS) synthesis. The aim of this study was to evaluate the synthesis of ROS in human umbilical vein endothelial cells (HUVECs) obtained from healthy newborns with (experimental) and without (control) a strong family history of type 2 DM, exposed to different glucose concentrations. HUVECs were exposed to various glucose concentrations for 24 and 48 h periods, before cell proliferation, mitochondrial activity, and mitochondrial membrane potential were determined. Intracellular ROS synthesis in the presence or absence of the mitochondrial uncoupler CCCP, cytochalasin B, or diphenyleneiodonium (DPI) was also evaluated. As opposed to control HUVECs, we found that experimental HUVECs exposed to 30 mmol/L glucose showed a 50% decrease in cell proliferation, a 90% reduction in mitochondrial activity, and a statistically significant inhibition of ROS synthesis in the presence of CCCP or cytochalasin B; DPI had no effect. Our results suggest that mitochondria and NAD(P)H-oxidase from HUVECs obtained from healthy newborns with a family history of DM have an innate deficient response to high glucose concentrations.

Retinol-Binding Protein 4 and Insulin Resistance in Lean, Obese, and Diabetic Subjects

Insulin resistance has a causal role in type 2 diabetes. Serum levels of retinol-binding protein 4 (RBP4), a protein secreted by adipocytes, are increased in insulin-resistant states. Experiments in mice suggest that elevated RBP4 levels cause insulin resistance. We sought to determine whether serum RBP4 levels correlate with insulin resistance and change after an intervention that improves insulin sensitivity. We also determined whether elevated serum RBP4 levels are associated with reduced expression of glucose transporter 4 (GLUT4) in adipocytes, an early pathological feature of insulin resistance. We measured serum RBP4, insulin resistance, and components of the metabolic syndrome in three groups of subjects. Measurements were repeated after exercise training in one group. GLUT4 protein was measured in isolated adipocytes. Serum RBP4 levels correlated with the magnitude of insulin resistance in subjects with obesity, impaired glucose tolerance, or type 2 diabetes and in nonobese, nondiabetic subjects with a strong family history of type 2 diabetes. Elevated serum RBP4 was associated with components of the metabolic syndrome, including increased body-mass index, waist-to-hip ratio, serum triglyceride levels, and systolic blood pressure and decreased high-density lipoprotein cholesterol levels. Exercise training was associated with a reduction in serum RBP4 levels only in subjects in whom insulin resistance improved. Adipocyte GLUT4 protein and serum RBP4 levels were inversely correlated. RBP4 is an adipocyte-secreted molecule that is elevated in the serum before the development of frank diabetes and appears to identify insulin resistance and associated cardiovascular risk factors in subjects with varied clinical presentations. These findings provide a rationale for antidiabetic therapies aimed at lowering serum RBP4 levels.

Plasma adiponectin concentration and tumor necrosis factor-α system activity in lean non-diabetic offspring of type 2 diabetic subjects

There is growing evidence that adiponectin function is related to the pathogenesis of insulin resistance. Insulin resistance might be present even in lean subjects with a strong family history of type 2 diabetes. The aim of the study was to look for adiponectin's role in the pathogenesis of insulin resistance in offspring of type 2 diabetic patients, and its relation to the activity of the tumor necrosis factor (TNF)-alpha system. The study was carried out in 23 lean offspring of type 2 diabetic subjects and in 23 controls matched for age, sex and body mass index. The oral glucose tolerance test for glucose and insulin estimations and hyperinsulinemic, euglycemic clamp studies were performed in all patients. The plasma concentration of adiponectin, TNF-alpha, soluble TNF receptors 1 and 2 (sTNFR1, sTNFR2), HbA1c, total cholesterol, high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein-cholesterol and triglycerides were estimated. The insulin sensitivity index, normalized for fat-free mass (M(ffm)) and adiponectin concentrations were markedly decreased in offspring of type 2 diabetic subjects compared with the control group (P = 0.0046 and P = 0.00058 respectively). TNF-alpha and sTNFR1 concentrations did not differ between the studied groups; however the concentration of sTNFR2 was markedly increased in the offspring of type 2 diabetic patients (P = 0.0002). Adiponectin concentration was positively correlated to the insulin sensitivity index (r = 0.34; P = 0.020) and to HDL-cholesterol (r = 0.29, P = 0.047) and was inversely related to sTNFR2 (r = -0.33, P = 0.027). The obtained results suggest that adiponectin could play a role in the pathogenesis of insulin resistance in lean offspring of type 2 diabetic subjects.