Late-onset Diabetes Research Articles

Diabetes and Insulin Secretion

The ATP-sensitive K+ channel (K ATP channel) senses metabolic changes in the pancreatic beta-cell, thereby coupling metabolism to electrical activity and ultimately to insulin secretion. When K ATP channels open, beta-cells hyperpolarize and insulin secretion is suppressed. The prediction that K ATP channel "overactivity" should cause a diabetic state due to undersecretion of insulin has been dramatically borne out by recent genetic studies implicating "activating" mutations in the Kir6.2 subunit of K ATP channel as causal in human diabetes. This article summarizes the emerging picture of K ATP channel as a major cause of neonatal diabetes and of a polymorphism in K ATP channel (E23K) as a type 2 diabetes risk factor. The degree of K ATP channel "overactivity" correlates with the severity of the diabetic phenotype. At one end of the spectrum, polymorphisms that result in a modest increase in K ATP channel activity represent a risk factor for development of late-onset diabetes. At the other end, severe "activating" mutations underlie syndromic neonatal diabetes, with multiple organ involvement and complete failure of glucose-dependent insulin secretion, reflecting K ATP channel "overactivity" in both pancreatic and extrapancreatic tissues.

IPF-1/MODY4 gene missense mutation in an Italian family with type 2 and gestational diabetes

Maturity-onset diabetes of the young (MODY) is a monogenic autosomal-dominant form of diabetes mellitus with onset before 25 years of age. Genetic variation in insulin promoter factor-1 ( IPF1) (MODY4) is uncommon but may contribute to early- or late-onset diabetes as part of a polygenic background. IPF1 is a homeodomain transcription factor required for pancreas development. Our aim was to identify whether IPF1 gene mutations play a role in Italian early-onset type 2 diabetic (T2D) patients and what functional impact mutations may have in the beta cell. We screened 40 Italian early-onset type 2 diabetic probands for IPF1 mutations, performed oral glucose tolerance tests in the unaffected family members, and performed in vitro functional studies of the mutant variant. In an extended family (Italy-6) of 46 members with clinical phenotypes of gestational diabetes, MODY, and T2D, a single nucleotide change of CCT to ACT was identified at codon 33 resulting in a Pro to Thr substitution (P33T) in the IPF1 transactivation domain that also contributes to an altered metabolic status in the unaffected NM subjects. Of the 22 genotyped Italy-6 members, 9 carried the P33T allele (NM), of whom 5 have either T2D or elevated fasting glucose levels. Oral glucose tolerance tests showed higher glucose levels at 90 minutes in unaffected NM compared with unaffected NN subjects. Of the 5 female pregnant carriers of the IPF1 mutation, 4 had pregnancies complicated by reduced birth weights, miscarriages, or early postnatal deaths. In studies in vitro, the IPF1 mutant protein (P33T) showed a reduction in DNA-binding and transcriptional activation functions as compared to the wild-type IPF1 protein. Our findings suggest that the P33T IPF1 mutation may provide an increased susceptibility to the development of gestational diabetes and MODY4 in the Italy-6 pedigree.

Lifetime risk of symptomatic carpal tunnel syndrome in Type 1 diabetes

To determine the lifetime risk of developing symptomatic carpal tunnel syndrome (CTS) in subjects with Type 1 diabetes and to investigate the effect of glycaemic control, body mass index (BMI), gender and age of onset of diabetes. One hundred and twenty-two consecutive subjects with Type 1 diabetes seen by a single investigator, over 1-year, were questioned about previous surgery for, or current symptoms of CTS. Those with current symptoms were referred for nerve conduction studies (NCS). Those with previous surgery and/or diagnostic NCS were classified as having CTS. Lifetime risk was calculated by the Kaplan-Meier method. Twenty six out of 122 patients had CTS, 18 of whom (69%) had undergone median nerve decompression surgery. The predicted lifetime risk of CTS reached 85% after 54 years of Type 1 diabetes (95% confidence interval: 72-97%). The duration of diabetes was greater in those who had developed CTS than in those who had not (29 vs. 19 years, P=0.0001). In those diagnosed with diabetes before the age of 20 there was a lag time of at least 19 years before the development of CTS, whereas patients with later onset of diabetes, began to develop CTS from as early as 5 years diabetes duration. There was no demonstrable effect of glycaemic control, obesity, gender or retinopathy on the appearance of CTS. The lifetime risk of developing symptomatic CTS with Type 1 diabetes is high, and is related to age and duration of diabetes, but not to the development of microvascular complications.

Alleles of the IL12B 3′UTR associate with late onset of type 1 diabetes

Carriage of a polymorphism in the 3′untranslated region of the IL12B gene encoding IL-12p40 was investigated in subjects with type 1 diabetes mellitus stratified by age at diagnosis ( n = 648) and compared with a population-based control cohort ( n = 246) residing in Western Australia. DNA samples were genotyped by polymerase chain reaction-restriction fragment length polymorphism or pyrosequencing. The C allele was more common in patients diagnosed after age 16 years than in controls (29% vs 17%, OR = 2.0, 95% CI = 1.4–2.7, p = 0.00003) or than in patients diagnosed when younger age 16 years (29% vs 22%, OR = 1.4, 95% CI = 1.1–1.9, p = 0.01). This reflected increases in homozygous and heterozygous carriage of the C allele. Heterozygosity was associated with a delayed disease in the late-onset diabetics ( p = 0.005; Student’s t-test). The effects of IL12B 3′untranslated region alleles on type 1 diabetes mellitus may reflect different levels of p40 available to form p40 homodimer, IL-12 (p35p40), and IL-23 (p19p40).

Genetic and perinatal factors as risk for childhood type 1 diabetes.

The mechanisms by which gestational infections, blood incompatibility, birth weight, mother's age and other prenatal or neonatal events increase the risk for type 1 diabetes are not understood. Studies so far have been retrospective, and there is a lack of population-based prospective studies. The possibility of identifying children at type 1 diabetes risk among first-degree relatives has resulted in prospective studies aimed at identifying postnatal events associated with the appearance of autoantibody markers for type 1 diabetes and a possible later onset of diabetes. However, the majority (85%) of new onset type 1 diabetes children do not have a first-degree relative with the disease. Population-based studies are therefore designed to prospectively analyse pregnant mothers and their offspring. One such study is DiPiS (Diabetes Prediction in Skåne), which is examining a total of about 10,000 pregnancies expected every year in the Skåne (Scania) region of Sweden that has 1.1 million inhabitants. Blood samples from all mothers in this region are obtained during pregnancy and at the time of delivery. Cord blood is analysed for HLA high-risk alleles and for autoantibodies against the 65 kD isoform of glutamic acid decarboxylase (GADA), the protein tyrosine phosphatase-related IA-2 antigen (IA-2A) and insulin (IAA) as a measure of prenatal autoimmune exposure. Identifying high-risk children by genetic, autoimmune and gestational risk factors followed by prospective analyses will make it possible to test the hypothesis that gestational events may trigger beta cell autoimmunity as a prerequisite for childhood type 1 diabetes.

Study of Tripterygium associated with nicotinamide in treating late-onset autoimmune diabetes mellitus in adults

Objective: To explore the effect of Tripterygium polyglycoside (TP) associated with nicotinamide on the islet cell function, immune parameters and lipoperoxide (LPO) in adult patients with late-onset autoimmune diabetes mellitus (LADA).Methods: Thirty-six cases of LADA were randomly divided into three groups: TP group (n = 12), treated with TP plus orally taken metformin; combined treatment group (n = 12), treated with TP combined with nicotinamide and metformin, and control group (n = 12) treated with metformin alone. They were followed-up for 18 months.Results: (1) Compared with the control group after 9 months of treatment, postprandial plasma glucose and LPO in combined treatment group were decreased (P <0.05), and the postprandial C-peptide was higher (P<0.05). At the 18th month, the value of postprandial C-peptide in the TP and combined treatment group was higher than that in the control group. The slL-2R level of both TP and combined treatment groups were lowered (P<0.01); (2) Islet cell antibody (ICA) positive of 5 cases in the TP group and 6 cases in the combined treatment group got converted to the negative respectively, while only one in the control group at the time (P<0.05); (3) The level of LPO in the combined treatment group was significantly lower than that in the TP group at the 18th month of treatment (P<0.05).Conclusion: TP combined with nicotinamide played a role in immunity regulation, decreasing the titer of islet cell antibody and slL-2R, which also reduced the production of LPO and had a tendency to improve islet cell function in early LADA patients.

Diversity of regulatory CD4+T cells controlling distinct organ-specific autoimmune diseases.

Depletion of selected regulatory CD4+ T cell subsets induces the spontaneous onset of various immune or autoimmune disorders. It is not clear, however, whether a given subset, notably CD4+CD25+ regulatory T cells, protects from a wide spectrum of immune disorders, or whether specialized subsets of regulatory T cells control each given disease or group of diseases. We report here, using diabetes prone nonobese diabetic (NOD) mice, that depending on the regulatory T cells that are depleted, i.e., CD25+, CD62L+, or CD45RB(low), distinct immune diseases appear after transfer into NOD severe combined immunodeficiency (SCID) recipients. Thus, reconstitution of NOD SCID mice with CD25- T cells induces major gastritis and late-onset diabetes, but no or mild colitis. Reconstitution with CD62L- T cells induces fulminant diabetes with no colitis or gastritis. Reconstitution with CD45RB(high) T cells induces major colitis with wasting disease and no or very moderate gastritis and diabetes. Major differences among the three regulatory T cell subsets are also seen in vitro. The bulk of suppressor cells inhibiting the proliferation of CD4+CD25- T cells in coculture is concentrated within the CD25+ but not the CD62L+ or CD45RB(low) T cell subsets. Similarly, cytokine production patterns are significantly different for each regulatory T cell subset. Collectively, these data point to the diversity and organ selectivity of regulatory T cells controlling distinct autoimmune diseases whatever the underlying mechanisms.

Familiality of metabolic abnormalities is dependent on age at onset and phenotype of the type 2 diabetic proband.

To determine the impact of a family history of the common form of type 2 diabetes and the phenotype of the proband on anthropometric and metabolic variables in normoglycemic first-degree relatives, we studied 2,100 first-degree relatives of patients with the common form of type 2 diabetes (FH+) and 388 subjects without a family history of diabetes (FH-). All subjects participated in an oral glucose tolerance test to allow measurement of insulin secretion [30-min incremental insulin/glucose (I/G 30)] and insulin sensitivity [homeostasis model assessment (HOMA) of insulin resistance (IR)]. A subset participated in a euglycemic clamp (n = 75) and an intravenous glucose tolerance test (n = 300). To study the effect of a particular phenotype of the proband, insulin secretion and sensitivity were also compared between first-degree relatives of diabetic probands with high and low waist-to-hip ratio (WHR) and probands with early and late onset of diabetes. FH+ subjects were more insulin resistant, as seen from a higher HOMA-IR index (P = 0.006) and a lower rate of insulin-stimulated glucose uptake (P = 0.001) and had more features of the metabolic syndrome (P = 0.02, P = 0.0002) compared with FH- subjects. Insulin secretion adjusted for insulin resistance (disposition index, DI) was also lower in the FH+ vs. FH- subjects (P = 0.04). Relatives of diabetic probands with a high WHR had reduced insulin-mediated glucose uptake compared with relatives of probands with a low WHR (P = 0.04). Relatives of diabetic patients with age at onset <44 yr had higher HOMA IR (P < 0.005) and lower DI (P < 0.005) than relatives of patients with age at onset >65 yr (highest quartile). We conclude that early age at onset of type 2 diabetes and abdominal obesity have a significant influence on the metabolic phenotype in the nondiabetic first-degree relative.

The incidence of diffuse idiopathic skeletal hyperostosis and social status correlations in Lithuanian skeletal materials

AbstractNumerous indications in literature argue that diffuse idiopathic skeletal hyperostosis (DISH) is aetiologically linked with obesity and late onset (type II) diabetes. Thus its incidence should differ in socially stratified societies where individuals have different access to food resources. The incidence of DISH was evaluated in a skeletal sample of 458 adult individuals from the Iron Age, Mediaeval, and Early Modern periods. Social status was defined either by grave inventory (Iron Age) or burial location (within a church, or urban or rural cemeteries). Diagnostic criteria for DISH were right side anterior longitudinal spinal ligament or extra‐spinal ligament (enthesis) ossification. No differences between chronological groups were found. The incidence of DISH had definite age affinity: it increased with age: from 0.00% in 20–30 year olds to 30.23% in the 50+ year old group (p&lt;0.001). It was also closely associated with sex: male/female ratio was 6.9 (p&lt;0.01). Social status was slightly but significantly related with DISH: incidence among high social status individuals was 27.14%, average or urban was 11.86%, poor or rural was 7.14% (p&lt;0.001). Our results confirm that DISH is associated with the male sex and advanced age and support the hypothesis that the incidence of DISH is related to life style, possibly as a result of different nutritional patterns. Copyright © 2003 John Wiley &amp; Sons, Ltd.

Insulin-like growth factor system gene expression in women with type 2 diabetes and breast cancer

Background/Aims: A twofold increased risk for breast cancer has been reported recently for women with late onset diabetes. Most studies showed that there were differences in serum concentrations of insulin-like...

Diabetic macular edema: review and update.

Impairment in the visual acuity and quality of life of diabetic patients with macular edema can undeniably be decreased with systemic and ocular therapeutic intervention, as shown by numerous controlled studies. Such interventions, with early screening and periodic examination, are even more crucial given the increasing survival of patients with diabetic retinopathy. In the 1950s, adjusted 5-year survival rates for patients with PDR were less than 30%, whereas by the end of the century age- and sex-adjusted 5-year survival rates approached 90% for patients with early-onset diabetes and 60% for patients with late-onset diabetes [83]. Furthermore, advances in our understanding of diabetic retinopathy have led to biochemical adjuncts that offer the potential for further reduction of visual loss caused by diabetic macular edema. Despite such advances, the implementation of effective treatments has been hampered by concerns over hypoglycemia after intensive insulin regimens, poor physician compliance regarding guidelines for dilated ophthalmic examinations, and economic barriers to access [84]. Therefore, it is imperative for the ophthalmologist not only to discuss the progression and treatment of diabetic macular edema and the importance of routine examination with patients but also to work with other health care professionals to ensure the evaluation and treatment of associated cardiovascular and neurologic disease. Educational programs, such as those created by the National Eye Health and Education Program [85], may also assist the ophthalmologist in providing patients with the optimal care available in the 21st century.

Role of exposure to air pollutants in the development of type 1 diabetes before and after 5 yr of age.

To assess the role of ambient air pollutants in type 1 diabetes in children. Prediagnosis exposure to five air pollutants was studied in two subgroups with onset of type 1 diabetes before and after 5 yr of age, and two matched subgroups of healthy children. Zip codes and dates of residence from birth to diagnosis were used to obtain geographic- and time-specific air concentrations of SO(2), NO(2), ozone (O(3)), SO(4), and particulate matter < 10 micro m in diameter (PM(10)). Prediagnosis time-adjusted pollutant exposure levels were created by summing up zip code-specific pollution data and dividing by months of exposure from birth to diagnosis. Two-tailed t-test and logistic regression were used to evaluate relative effects and test data between cases and controls. Prediagnosis average O(3) exposure was significantly higher in children with type 1 diabetes than in healthy controls. Prediagnosis PM(10) exposure was significantly higher in children diagnosed before 5 yr of age, when compared with healthy controls. SO(2) exposure was significantly higher in children with later-onset diabetes compared with those with early-onset diabetes (EOD). NO(2), SO(2) and SO(4) exposure was significantly lower in children diagnosed after 5 yr of age, when compared with healthy controls. O(3), NO(2), SO(4) and PM(10) levels did not significantly differ between the two diabetic subgroups. Increased ozone exposure may be a contributory factor to the increased incidence of type 1 diabetes. PM(10) may be a specific contributory factor to the development of type 1 diabetes before 5 yr of age.

Long-term results of distal pancreatectomy for chronic pancreatitis in 90 patients.

To determine the indications for distal pancreatectomy for chronic pancreatitis and to evaluate the risks, functional loss, and outcome of the procedure. Chronic pancreatitis is generally associated with continued pain, parenchymal and ductal hypertension. and progressive pancreatic dysfunction, and it is a cause of premature death in patients who receive conservative treatment. Good results have recently been reported by the authors and others for resection of the pancreatic head in this disease, but distal pancreatectomy is a less popular option attended by variable success rates. It remains a logical approach for patients with predominantly left-sided pancreatic disease, however. A personal series of 90 patients undergoing distal pancreatectomy for chronic pancreatitis over the last 20 years has been reviewed, with a mean postoperative follow-up of 34 months (range 1-247). Pancreatic function was measured before and after operation in many patients. Forty-eight of 84 patients available for follow-up had a successful outcome in terms of zero or minimal, intermittent pain. There was one perioperative death, but complications developed in 29 patients, with six early reexplorations. Morbidity was unaffected by associated splenectomy or right-to-left dissection. Late mortality rate over the follow-up period was 10%; most of these late deaths occurred because of failure to abstain from alcohol. Preoperative exocrine function was abnormal in two thirds of those tested and was unchanged at follow-up. Diabetic curves were seen in 10% of patients preoperatively, while there was an additional diabetic morbidity rate of 23% related to the procedure and late onset of diabetes (median duration 27 months) in another 23%. Diabetic onset was related to percentage parenchymal resection as well as splenectomy. Outcome was not clearly dependent on the etiology of pancreatitis or on disease characteristics as assessed by preoperative imaging. However, patients with pseudocyst disease alone did better than other groups. Twenty-one of 36 patients who failed to respond to distal pancreatectomy required further intervention, including completion pancreatectomy, neurolysis, and sphincteroplasty. Thirteen of these 21 patients achieved long-term pain relief after their second procedure. Distal pancreatectomy for chronic pancreatitis from any etiology can be performed with low mortality and a good outcome in terms of pain relief and return to work in approximately 60% of patients. Little effect is seen on exocrine function of the pancreas, but there is a diabetic risk of 46% over 2 years. Pseudocyst disease is associated with the best outcome, but other manifestations of this disease, including strictures, calcification, and limited concomitant disease in the head of the pancreas, can still be associated with a good outcome.

Areca nut use following migration and its consequences.

Areca nut use is widespread in the Oriental countries, affecting approximately 20% of the world's population. The combined use of areca nut and smokeless tobacco (ST) is practiced particularly in the Indo-Chinese continents. While there is considerable global variation in the use of these products, migrant studies relevant to areca nut use is of considerable interest to epidemiologists in suggesting the extent to which these environment exposures are important in the aetiology of different cancers and other health-related consequences. Studies on Indian migrants to the Malay peninsula, South and east Africa and various Asian ethnic groups resident in several parts of the United Kingdom have shown that the consumption of areca nut (often mixed with ST) is highly prevalent in these communities. Available data on the prevalence of areca chewing among these migrant populations are reviewed here. The carriage of these risk factors from South Asia to other countries has resulted in excess risk of oral cancer in these new settlements. There is also a high incidence of cardiovascular disease, hypertension and late onset diabetes among Indians living in the United Kingdom and there is new evidence to suggest that the combined roles of areca and ST may be contributory. Because of their enhanced financial situation, substance abuse may increase in their new country of domicile. The two products are psychologically addictive and a dependency syndrome related to their use among Asian immigrants to the United Kingdom has been described recently.

Studies of the variability of the hepatocyte nuclear factor-1beta (HNF-1beta / TCF2) and the dimerization cofactor of HNF-1 (DcoH / PCBD) genes in relation to type 2 diabetes mellitus and beta-cell function.

Mutations in the homeodomain-containing transcription factor hepatocyte nuclear factor-1beta (HNF-1beta) are known to cause a rare subtype of maturity-onset diabetes of the young (MODY5), which is associated with early-onset progressive non-diabetic renal dysfunction. To investigate whether mutations in HNF-1 are implicated in the pathogenesis of MODY or late-onset diabetes with and without nephropathy in Danish Caucasians we examined the HNF-1beta (TCF2) and the dimerization cofactor of HNF-1 (DCoH, PCBD) genes for mutations in 11 MODY probands, 28 type 2 diabetic patients with nephropathy, and 46 type 2 diabetic patients with an impaired beta-cell function by combined single-strand conformation polymorphism (SSCP) and heteroduplex analysis. Analysis of the promoter and nine exons including intron-exon boundaries of the HNF-1beta gene revealed one novel silent polymorphism and three previously reported intronic variants. The silent polymorphism (I91I) was found in one patient with late-onset type 2 diabetes. One of the intronic variant (IVS6+26T-->C) was examined further. Among 584 type 2 diabetic patients the allelic frequency was 13.1% (11.2-15.0%) compared to 11.6% (8.6-14.5%) in 229 glucose tolerant control subjects (NS). No difference in insulin secretion during an OGTT was seen between carriers of the different IVS6+26T-->C genotypes among the 229 middle-aged control subjects, nor among 302 glucose tolerant 60-year-old Danish Caucasians. Mutation analysis of the four exons comprising the DCoH gene revealed a previously described A-->G polymorphism located in the 3' untranslated region, which was not investigated further. In conclusion, mutations in HNF-1beta and DCoH are not a major cause of MODY or late onset type 2 diabetes in Danish Caucasian subjects.

Angiocentric T-cell lymphoma of the pancreas presenting as late-onset diabetes mellitus with diabetic retinopathy

Pancreatic lymphoma presenting with clinical diabetes mellitus (DM) is rare. We report angiocentric T-cell lymphoma of the pancreas in a 65-year-old Thai woman who presented with progressive deterioration of visual acuity of both eyes. She had diabetic retinopathy (DR) diagnosed only 20 months after the diagnosis of DM at the age of 63. She later developed erythematous rashes, fever, and deterioration of consciousness; she eventually died of shock. A skin biopsy and bone marrow examination revealed angiocentric T-cell lymphoma. At autopsy, the pancreas and both eyes were extensively infiltrated by lymphoma. Widespread involvement of nearly all organs but superficial lymphadenopathy was detected. In contrast to other typical cases of long-standing DM, only mild atherosclerosis was noted, and no DR was found. To the best of our knowledge, this is the first case of lymphoma involving the pancreas and both eyes producing clinical DM and DR. HUM PATHOL 32:741-745. Copyright © 2001 by W.B. Saunders Company

Is It Sick to Want to Live to 100? The Popular Culture of Health and Longevity

Is It Sick to Want to Live to 100? The Popular Culture of Health and Longevity

Mutation screening of the hepatocyte nuclear factor (HNF)-6 gene in Japanese subjects with diabetes mellitus

Heterozygous mutations in the genes encoding transcription factors (HNF-1α, HNF-1β and HNF-4α) in the hepatocyte nuclear factor (HNF) network are associated with maturity-onset diabetes of the young (MODY). We screened HNF-6 gene for mutations in 34 Japanese subjects with MODY/early-onset diabetes mellitus and 56 subjects with late-onset diabetes mellitus. One single nucleotide polymorphism (SNP) at codon 287 (GGG to GGT) was found in the gene and the frequency was similar among MODY/early-onset diabetes, late-onset diabetes and control subjects. Genetic variations in the HNF-6 gene are not likely to contribute to the susceptibility to diabetes mellitus in Japanese.

Contraindication of magnesium sulfate in a pregnancy complicated with late-onset diabetes mellitus and sensory deafness due to mitochondrial myopathy

Contraindication of magnesium sulfate in a pregnancy complicated with late-onset diabetes mellitus and sensory deafness due to mitochondrial myopathy

Academic and Social Experiences of Children With Insulin-Dependent Diabetes Mellitus

The academic and social experiences of children with and without insulin-dependent diabetes mellitus were investigated. Measures included the Wechsler Intelligence Scale for Children-III, the Peabody Individual Achievement Test-Revised, and a parent interview. Results indicated that children with diabetes scored lower on some cognitive and academic measures compared to children without diabetes, but their school and social life was not remarkably different. Few differences were found between children with early onset and late onset of diabetes. The findings suggest that poorer management of diabetes is associated with greater school absences, which in turn are associated with lower grades in school.