Late-onset Diabetes Research Articles

Is there a relationship between stature and age of onset of type 2 Diabetes?

AimsMSP1A and MSP1B polymorphic sites located in the GH genomic area have been found associated with GH response to insulin stimulation, with familiar short stature and with age at onset of Type 2 Diabetes (T2D). These observations prompted us to search for a possible relationship between stature and age at onset of the disease. MethodsWe have reexamined the data of 272 subjects with T2D mellitus. ResultsThere is a highly significant negative correlation between stature and age at onset in non obese females (p < 0.001) but not in obese females and in males. In non obese females with stature within the first quartile the mean age at onset is 62 years while in those with a stature greater than the first quartlile the mean age at onset is 52 yesrs (p < 0.001). No difference is observed in obese females and males. ConclusionsThese observations suggest the existence of different mechanisms underlying susceptibility to T2D. In addition to the well known increased risk due to obesity, endocrine dysfunctions related to genetic variability within the GH genomic area could represent another mechanism operating in non obese females. A cluster of non obese women characterized by short stature and late onset of diabetes seems to be separated by this mechanism from other women.

Diabetes Mellitus After Pediatric Kidney Transplant.

Kidney transplant is the best renal replacement therapy for pediatric patients with end-stage renal disease; however, this procedure is not without complications. A major complication is the development of new-onset diabetes mellitus, which affects the outcomes of transplant in terms of kidney and patient survival. In this study, our objective was to calculate the percentage of pediatric patients who developed new-onset diabetes mellitus or transient hyperglycemia after kidney transplant, compare our data with international data, and discuss the related factors that predispose to diabetes. A retrospective study was conducted by reviewing the medical records of pediatric patients who had transplant procedures or were followed at the Royal Medical Services (Amman, Jordan) from 2007 to 2017. Our study cohort included 104 patients. The average follow-up time was 4 years and 7 months, with a maximum follow-up of 9 years. Ten patients developed posttransplant hyperglycemia, with 8 developing early hyperglycemia (during the first 3 months posttransplant). In 40% of patients, this complication was transient, and patients stopped insulin after immunosuppressant medications were decreased. However, 60% of patients continued to have diabetes, with 20% having late-onset diabetes and treatment with oral hypoglycemic agent. Pretransplant awareness of risk factors of new-onset diabetes mellitus after transplant and close monitoring of hyperglycemia during the posttransplant period are mandatory. Transient hyperglycemia after kidney transplant is common, and kidney transplant does not alleviate the high risk of diabetes in patients with chronic kidney disease.

An Atypical HNF4A Mutation Which Does Not Conform to the Classic Presentation of HNF4A-MODY

Objective To present the case of an atypical Hepatocyte Nuclear Factor 4 Alpha (HNF4A) mutation that is not consistent with the classically published presentation of HNF4A-Mature Onset Diabetes of the Young (MODY). Methods Clinical presentation and literature review. Results A 43-year-old nonobese man was referred to the endocrinology clinic for evaluation of elevated fasting blood glucose (FBG) measurements. Laboratory review revealed prediabetes and hypertriglyceridemia for the previous decade. Testing of autoantibodies for type 1 diabetes was negative. Genetic testing showed an autosomal dominant, heterozygous missense mutation (c.991C>T; p.Arg331Cys) in the HNF4A gene, which is correlated with HNF4A-MODY. Phenotypically, patients with an HNF4A-MODY tend to have early-onset diabetes, microvascular complications, low triglyceride levels, increased birth weight, fetal macrosomia, and less commonly neonatal hyperinsulinemic hypoglycemia. The patient did not demonstrate any of these features but instead presented with late-onset diabetes, an elevated triglyceride level, and a normal birth weight. Conclusion Our patient likely represents an atypical variant of HNF4A-MODY with a milder clinical presentation. Patients with atypical, less-severe presentations of HNF4A-MODY may be largely undiagnosed or misdiagnosed, but identification is important due to implications for treatment, pregnancy, and screening of family members.

SILAC-based quantitative proteomic analysis of the livers of spontaneous obese and diabetic rhesus monkeys.

Type 2 diabetes mellitus (T2DM) is a severe metabolic disorder that affects more than 10% of the population worldwide. Obesity is a major cause of insulin resistance and contributes to the development of T2DM. Liver is an essential metabolic organ that plays crucial roles in the pathogenesis of obesity and diabetes. However, the underlying mechanisms of liver in the transition of obesity to diabetes are not fully understood. The nonhuman primate rhesus monkey is an appropriate animal for research of human diseases. Here, we first screened and selected three individuals of spontaneously diabetic rhesus monkeys. Interestingly, the diabetic monkeys were obese with a high body mass index at the beginning, but gradually lost their body weight during one year of observation. Furthermore, we performed stable isotope labeling with amino acids in cell culture-based quantitative proteomics to identify proteins and signaling pathways with altered expression in the liver of obese and diabetic monkeys. In total, 3,509 proteins were identified and quantified, of which 185 proteins displayed an altered expression level. Gene ontology analysis revealed that the expression of proteins involved in fatty acids β-oxidation and galactose metabolism was increased in obese monkeys; while proteins involved in oxidative phosphorylation and branched chain amino acid (BCAA) degradation were upregulated in diabetic monkeys. In addition, we observed mild apoptosis in the liver of diabetic monkeys, suggesting liver injury at the late onset of diabetes. Taken together, our liver proteomics may reveal a distinct metabolic transition from fatty acids β-oxidation in obese monkey to BCAA degradation in diabetic monkeys.

Longitudinal Study of Rhesus Monkeys Determines That Amylase and Lipase Levels Are Significant Risk Factors for Type 2 Diabetes Mellitus

Decreased levels of amylase have been reported in type 2 diabetes (T2DM), however, longitudinal within subject study ranging from healthy normal levels to preT2DM and overt DM has not previously been conducted in humans or in nonhuman primates. Rhesus monkeys provide the ideal subjects for this study as they are maintained under constant dietary and environmental conditions, and have, to date, been shown to have the same gastrointestinal/pancreas physiology and pathophysiology as humans. They frequently develop T2DM spontaneously and naturally, with no experimental intervention, and with life time rates of T2DM estimated to be 20 to 30 %. Adult rhesus monkeys were studied for a minimum of 3 years and a maximum of 20 years, with a minimum of 2 metabolic parameter measurements per year. These parameters included fasting plasma glucose (FPG), fasting plasma insulin (FPI), complete blood chemistry, and lipid profiles. Body fat was determined by the tritiated water dilution method or by the dual energy xray absorptiometry (DEXA). Insulin sensitivity was quantified by the euglycemic hyperinsulinemic clamp method. These parameters were used to identify the phases in the progression of monkeys from normal to overt diabetes as follows: normal = phases 1–3; metabolic syndrome = phases 4–6, impaired glucose tolerance= phase 7, and overt type 2 diabetes = phase 8. Diabetic monkeys requiring insulin treatment were excluded from this study. Human criteria were used to define MetSyn, IGT and T2DM. Normal healthy serum amylase levels were determined for the first time and shown to be 253 ±5.1 U/L for adults 7 to 11 yrs old (“human years” about 21 to 35 yrs), with normal lipase levels of 29.7± 1.6 U/L. Serum amylase levels declined with age by about 25%, with no change in serum lipase levels with age. In those that progressed through phases 4 to 8 reaching overt type 2 diabetes, serum amylase showed significantly greater declines from ages 13 to 20 yrs with progressive and parallel declines in metabolic parameters, including insulin sensitivity, and HDL cholesterol levels and increases in serum triglycerides and subsequently increases in fasting plasma glucose. The significant rise in serum triglycerides and the decline in amylase together serve as excellent early predictors of the progression to overt T2DM. These risk factors were highly predictive of both early and late onset diabetes. The lower amylase levels observed previously in people with diabetes were clearly not a consequence of diabetes, but were in fact markers of impending diabetes. Such biomarkers are likely to be useful in predicting the development of T2DM in patients years before the disease becomes overt.This study was carried out in accord with the FASEB principles for the use of animals in research.Support or Funding InformationThe work was supported by NIA N01AG31012 and NIA HHSN2532008002C to BCH, and the Department of Health Research, Government of India Human Resources Development Fellowship to UKC.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Ocular findings in Zucker Diabetic Fatty rats emphasize the key role of neuroglia degeneration in diabetic retinopathy pathophysiology.

Ocular findings in Zucker Diabetic Fatty rats emphasize the key role of neuroglia degeneration in diabetic retinopathy pathophysiology.

Young onset type 2 diabetic patients might be more sensitive to metformin compared to late onset type 2 diabetic patients

It is unknown whether YOD (young onset diabetes) and LOD (late onset diabetes) require similar insulin doses for intensive insulin therapy with a metformin add-on to achieve glycemic control. We analyzed data from our two previously performed randomized, controlled open-label trials. Patients were randomized to receive either continuous subcutaneous insulin infusion (CSII) therapy or CSII combined with metformin therapy for 4 weeks. The studies concentrated on the differences in the insulin doses used for the two groups. We included 36 YOD (age < 40 yrs) and 152 LOD (age > 40 yrs) patients. YOD patients who received metformin combined with CSII therapy required significantly lower insulin doses to maintain euglycemic control compared to patients with LOD. A multivariate analysis, controlled for gender and the fasting blood concentration, was performed to determine the significance of the differences between groups, particularly with respect to the total and basal insulin doses. There was a trend toward improvement in β-cell function and insulin resistance in terms of ΔHOMA-B and ΔHOMA-IR in patients with YOD compared to those with LOD. Newly diagnosed T2D patients with YOD required significantly lower insulin doses, particularly basal insulin doses, to maintain glycemic control compared to the LOD patients.

High risk of conversion to diabetes in first-degree relatives of individuals with young-onset type 2 diabetes: a 12-year follow-up analysis.

Family history of diabetes is an established risk factor for Type 2 diabetes, but the impact of a family history of young-onset diabetes (onset < 40 years) on future risk of diabetes among first-degree relatives is unclear. In this prospective study, we examined the influence of family history of late- versus young-onset diabetes on the development of diabetes in a young to middle-aged Chinese population. Some 365 siblings identified through probands with Type 2 diabetes and 452 participants from a community-based health awareness project (aged 18-55 years) who underwent metabolic assessment during the period 1998-2002 were followed to 2012-2013 to determine their glycaemic status. Multivariate logistic regression was performed to investigate the association of family history of diabetes presented at different age categories with development of diabetes. In this cohort, 53.4% (n = 167) of participants with a family history of young-onset diabetes, 30.1% (n = 68) of those with a family history of late-onset diabetes and 14.4% (n = 40) of those without a family history developed diabetes. Using logistic regression, family history of diabetes presented at ages ≥ 50, 40-49, 30-39 and < 30 years, increased conversion to diabetes with respective odds ratios of 2.4, 5.8, 9.4 and 7.0 (P < 0.001 for all), after adjustment for socio-economic status, smoking, obesity, hypertension and dyslipidaemia. Among participants without diabetes at baseline, risk association of family history of late-onset diabetes with incident diabetes was not sustained, whereas that of family history of young-onset diabetes remained robust on further adjustment for baseline glycaemic measurements. First-degree relatives of people with Type 2 diabetes, especially relatives of those with young-onset diabetes, are at high risk for diabetes.

Incidence of diabetes-related complications in Chinese patients with type 1 diabetes: a population-based longitudinal cohort study in Taiwan

ObjectiveTo estimate the incidence densities and cumulative incidence of diabetes-related complications in patients with type 1 diabetes for a maximum of 15-year follow-up. The estimations were further stratified by gender...

Albuminuria in patients with young onset type 2 diabetes

Introduction: Findings from several studies have indicated that patients with young onset diabetes (YOD) are more likely than those with late-onset diabetes (LOD) to have poor metabolic control and more diabetes-associated complications. Objectives: This study was to assess assess the profile at admission and the evolution in a cohort of young patients presenting type 2 diabetes (T2D) and to study the influence of glycemic control on progression of albuminuria. Patients and Methods: This is a prospective study. Inclusion criteria targeted patients who had T2D diagnosed before the age of 40 years and had been regularly followed in nephrology consultation for at least 36 months. Results: A total of 121 patients met the inclusion criteria. Mean age at diabetes diagnosis was 39 ± 3 years and 64.5% were female. Mean body mass index (BMI) was 28.02 ± 4.47 kg/m2. 22.3%, 57.9% and 19.8% had respectively, negative, micro- and macro-albuminuria. 22.3% were hypertensive, 36.4% had controlled diabetes and 14.9% had an estimated glomerular filtration rate (GFR) of <60 mL/min/m2. At the end of follow-up, 27.3% were hypertensive, 24% had controlled diabetes, 27.3% had negative albuminuria, 17.4% showed rapid renal progression and cardiovascular events occurred in 12.4% of cases. Conclusion: Control of blood pressure, glycemia and albuminuria remain difficult to achieve in adults with YOD type 2, thus exacerbating the renal and cardiovascular disease (CVD) risk

Diagnosing gestational diabetes mellitus: implications of recent changes in diagnostic criteria and role of glycated haemoglobin (HbA1c)

Gestational diabetes mellitus (GDM; approximately 5% of pregnancies) represents the most important risk factor for development of later-onset diabetes mellitus. We examined concordance between GDM diagnosis defined using the original 1999 World Health Organization (WHO) criteria and the more recent 2013 WHO criteria and 2015 National Institute for Health and Care Excellence (NICE) criteria. We studied two groups: a case-control group of 257 GDM positive and 266 GDM negative cases, and an incident cohort 699 GDM positive and 6,231 GDM negative cases. In the incident cohort, GDM prevalence was 3.7% (WHO 1999 criteria), 11.4% (NICE 2015 criteria) and 13.7% (WHO 2013 criteria). Our results showed that a significant number of additional cases are detected using the more recent NICE and WHO criteria than the original 1999 WHO criteria, but these additional cases represent an intermediate group with 'moderate' dysglycaemia (abnormal blood glucose levels). Our results also show that use of these newer criteria misses a similar group of intermediate cases that were defined as GDM by the 1999 WHO criteria and that glycated haemoglobin in isolation is unlikely to replace the oral glucose tolerance test in GDM diagnosis.

Two novel RFX6 variants in siblings with Mitchell-Riley syndrome with later diabetes onset and heterotopic gastric mucosa

Mitchell-Riley syndrome, an autosomal recessive disorder caused by mutations in the RFX6 gene, is defined as a combination of neonatal diabetes mellitus and serious congenital gastrointestinal defects. We describe Mitchell-Riley syndrome in two sisters with two novel compound heterozygous variants in the RFX6 gene: c.1154G > A, p.(Arg385Gln), and c.1316_1319delTCTA, p.(Ile439Thrfs*13). Both sisters present milder forms of the syndrome, likely due to possible residual activity of the p.Arg385Gln variant, which is localized in a dimerization domain of the RFX6 transcription factor. We propose that the prognosis is dependent on patient RFX6 genotype and possible residual activity of RFX6 transcription factor. Both sisters had atypical later onset of diabetes, at 2 years and 10 months and 2 years and 7 months, respectively. This supports the need of extending the definition of diabetes in Mitchell-Riley syndrome from neonatal to childhood onset and regular glyceamia check in patients with gastrointestinal tract malformations typical for Mitchell-Riley syndrome. The clinical course in both sisters improved significantly after surgical removal of parts of the small intestine with heterotopic gastric mucosa. We suggest that gastric mucosa heterotopy is an important actionable part of Mitchell-Riley syndrome and could have been responsible for the malabsorption, failure to thrive and severe anemia present in previously reported patients with Mitchell-Riley syndrome.

Factors associated with abnormal cardio-ankle vascular index in patients with type 2 diabetes and prediabetes

Aim: The purpose of this study was to examine the phenotypic and genetic characteristics of patients with type 2 diabetes mellitus (T2DM) with different responses to treatment with metformin (MF) in the Novosibirsk region. Materials and methods: We examined 460 patients with T2DM in the Novosibirsk region. Patients were divided into groups according to their HbA1c level: patients who achieved the target HbA1c level during MF therapy (n = 209) and those who did not reach the target HbA1c level (n=251). Genotyping of ATM (rs11212617) was performed using polymerase chain reaction by TaqMan. Results: Patients who achieved the target HbA1c level during MF treatment (good response) were older (61. 1±9. 1 years vs. 57. 4±8. 4 years, p=0. 001), had later onset of diabetes (54. 6 ± 10. 1 years vs. 49. 2±8. 5 years, p = 0. 0001) and shorter duration of diabetes (6. 5±5. 9 years vs. 8. 2±6. 1 years, p=0. 03) compared with those who did not achieve the target HbA1c level. There was no statistically significant association between ATM rs11212617 and achieving the target HbA1c level among all patients [odds ratio (OR)=0. 94, 95% confidence interval = (0. 73–1. 23), p=0. 67] or those with MF monotherapy [OR=0. 90, (0. 65–1. 25), p=0. 54] or combination therapy [OR=1. 02, (0. 72–1. 43), p=0. 92]. There was an effect of age on response to MF therapy in all three groups (all patients: p=0. 001, MF monotherapy group: p=0. 04, combination therapy group: p=0. 0009). In the MF monotherapy group, low dose MF was associated with a good response (p=0. 03), and in the combination therapy group, males were more likely to have a good response (p=0. 003). Patients with genotype C/C or A/C for ATM (rs11212617) compared with those with genotype A/A were more likely to have high levels of triglycerides [2. 33 (1. 52–4. 2) mmol/l, 2. 09 (1. 35–3. 0) mmol/l and 1. 99 (1. 49–3. 21) mmol/l, respectively, p=0. 001], coronary heart disease (CHD) (13. 4%, 13. 4% and 9. 6%, respectively, p=0. 009) and myocardial infarction (7. 8%, 3. 2% and 4. 0%, respectively, p=0. 001). Conclusion: Patients with T2DM who had a good response to MF therapy were older, more likely to be male and had a later onset of T2DM. Genotype C/C for ATM rs11212617 was associated with high triglycerides, CHD and myocardial infarction. ATM rs11212617 was not associated with response to MF therapy in the Novosibirsk region.

Phenotypic and genetic characteristics of patients with type 2 diabetes with different responses to metformin therapy in Novosibirsk region

Aim: The purpose of this study was to examine the phenotypic and genetic characteristics of patients with type 2 diabetes mellitus (T2DM) with different responses to treatment with metformin (MF) in the Novosibirsk region. Materials and methods: We examined 460 patients with T2DM in the Novosibirsk region. Patients were divided into groups according to their HbA1c level: patients who achieved the target HbA1c level during MF therapy (n = 209) and those who did not reach the target HbA1c level (n=251). Genotyping of ATM (rs11212617) was performed using polymerase chain reaction by TaqMan. Results: Patients who achieved the target HbA1c level during MF treatment (good response) were older (61. 1±9. 1 years vs. 57. 4±8. 4 years, p=0. 001), had later onset of diabetes (54. 6 ± 10. 1 years vs. 49. 2±8. 5 years, p = 0. 0001) and shorter duration of diabetes (6. 5±5. 9 years vs. 8. 2±6. 1 years, p=0. 03) compared with those who did not achieve the target HbA1c level. There was no statistically significant association between ATM rs11212617 and achieving the target HbA1c level among all patients [odds ratio (OR)=0. 94, 95% confidence interval = (0. 73–1. 23), p=0. 67] or those with MF monotherapy [OR=0. 90, (0. 65–1. 25), p=0. 54] or combination therapy [OR=1. 02, (0. 72–1. 43), p=0. 92]. There was an effect of age on response to MF therapy in all three groups (all patients: p=0. 001, MF monotherapy group: p=0. 04, combination therapy group: p=0. 0009). In the MF monotherapy group, low dose MF was associated with a good response (p=0. 03), and in the combination therapy group, males were more likely to have a good response (p=0. 003). Patients with genotype C/C or A/C for ATM (rs11212617) compared with those with genotype A/A were more likely to have high levels of triglycerides [2. 33 (1. 52–4. 2) mmol/l, 2. 09 (1. 35–3. 0) mmol/l and 1. 99 (1. 49–3. 21) mmol/l, respectively, p=0. 001], coronary heart disease (CHD) (13. 4%, 13. 4% and 9. 6%, respectively, p=0. 009) and myocardial infarction (7. 8%, 3. 2% and 4. 0%, respectively, p=0. 001). Conclusion: Patients with T2DM who had a good response to MF therapy were older, more likely to be male and had a later onset of T2DM. Genotype C/C for ATM rs11212617 was associated with high triglycerides, CHD and myocardial infarction. ATM rs11212617 was not associated with response to MF therapy in the Novosibirsk region.

Identification of HNF4A Mutation p.T130I and HNF1A Mutations p.I27L and p.S487N in a Han Chinese Family with Early-Onset Maternally Inherited Type 2 Diabetes.

Maturity-onset diabetes of the young (MODY) is characterized by the onset of diabetes before the age of 25 years, positive family history, high genetic predisposition, monogenic mutations, and an autosomal dominant mode of inheritance. Here, we aimed to investigate the mutations and to characterize the phenotypes of a Han Chinese family with early-onset maternally inherited type 2 diabetes. Detailed clinical assessments and genetic screening for mutations in the HNF4α, GCK, HNF-1α, IPF-1, HNF1β, and NEUROD1 genes were carried out in this family. One HNF4A mutation (p.T130I) and two HNF1A polymorphisms (p.I27L and p.S487N) were identified. Mutation p.T130I was associated with both early-onset and late-onset diabetes and caused downregulated HNF4A expression, whereas HNF1A polymorphisms p.I27L and p.S487N were associated with the age of diagnosis of diabetes. We demonstrated that mutation p.T130I in HNF4A was pathogenic as were the predicted polymorphisms p.I27L and p.S487N in HNF1A by genetic and functional analysis. Our results show that mutations in HNF4A and HNF1A genes might account for this early-onset inherited type 2 diabetes.

Variation in sleep is associated with diagnosis of late-onset diabetes: a cross-sectional analysis of self-reported data from the first wave of ‘Understanding Society’ (the UK Household Longitudinal Study)

Variation in sleep is associated with diagnosis of late-onset diabetes: a cross-sectional analysis of self-reported data from the first wave of ‘Understanding Society’ (the UK Household Longitudinal Study)

Risk of non-fatal cardiovascular diseases in early-onset versus late-onset type 2 diabetes in China: a cross-sectional study

The age of onset of type 2 diabetes is decreasing. Because non-Chinese patients with early-onset type 2 diabetes (defined here as diagnosis at <40 years) have increased risk of vascular complications, we investigated effects of early-onset versus late-onset type 2 diabetes on risk of non-fatal cardiovascular diseases in China. We did a cross-sectional survey using data from the China National HbA1c Surveillance System (CNHSS), including 222,773 Chinese patients with type 2 diabetes in 630 hospitals from 106 cities in 30 provinces of China in 2012. We documented demographic information and clinical profiles. Non-fatal cardiovascular disease was defined as non-fatal coronary heart disease or non-fatal stroke. Prevalence of non-fatal cardiovascular diseases was standardised to the Chinese population in 2011. We did logistic regression analysis to obtain odds ratios (ORs) for the risk of cardiovascular disease in patients with early-onset versus late-onset type 2 diabetes. Because the CNHSS did not contain patients on diet or lifestyle treatment alone, and did not capture information on smoking or lipid or antihypertensive treatment, we validated our findings in another dataset from a cross-sectional, multicentre observational study (the 3B study) of outpatients with type 2 diabetes to confirm that exclusion of patients with diet treatment only and non-adjustment for lipid-lowering and antihypertensive drugs did not introduce major biases in the main analysis. Of 222,773 patients recruited from April 1, 2012, to June 30, 2012, 24,316 (11%) had non-fatal cardiovascular disease. Patients with early-onset diabetes had a higher age-adjusted prevalence of non-fatal cardiovascular disease than did patients with late-onset diabetes (11·1% vs 4·9%; p<0·0001). After adjustment for age and sex, patients with early-onset type 2 diabetes had higher risk of non-fatal cardiovascular disease than did those with late-onset type 2 diabetes (OR 1·91, 95% CI 1·81-2·02). Adjustment for duration of diabetes greatly attenuated the effect size for risk of non-fatal cardiovascular disease (1·13, 1·06-1·20). Results of the validation study showed that exclusion of patients with diet only and non-adjustment for lipid-lowering and antihypertensive drugs resulted in marginal changes in ORs for risk of non-fatal cardiovascular disease in patients with early-onset versus late-onset type 2 diabetes. Early-onset type 2 diabetes remained associated with increased risk of cardiovascular disease, attributable to longer duration of diabetes. Chinese patients with early-onset type 2 diabetes are at increased risk of non-fatal cardiovascular disease, mostly attributable to longer duration of diabetes. Novo Nordisk China (for the China National HbA1c Surveillance System [CNHSS]) and Merck Sharp & Dohme China (for the 3B study).

Diabetes and Onset of Natural Menopause

The age at natural menopause (ANM) in the Western world ranges from 40 to 60 years, with an average onset of 51 years. The exact mechanisms underlying the timing of ANM are not completely understood. Both genetic and environmental factors are involved. The best-established environmental factor affecting ANM is smoking; menopause occurs 1 to 2 years earlier in smokers. In addition to genetic and environmental factors, chronic metabolic diseases may influence ANM. Some evidence suggests that diabetes may accelerate menopausal onset. With more women of childbearing age receiving a diagnosis of diabetes, it is important to examine the impact of diabetes on reproductive health. This study was designed to determine whether ANM occurs at an earlier age among women who have diabetes before menopause than in women without diabetes. Data were obtained from the European Prospective Investigation into Cancer and Nutrition (EPIC) study, a large multicenter prospective cohort study investigating the relationship between diet, lifestyle, and genetic factors and the incidence of cancer and other chronic diseases. A cohort of 519,978 men and women, mostly aged 27 to 70 years, were recruited primarily from the general population between 1992 and 2000. A total of 367,331 women participated in the EPIC study. After exclusions, 258,898 of these women met study inclusion criteria. Diabetes status at baseline and menopausal age were based on self-report and were obtained through questionnaires. Participants were asked if they had ever been diagnosed with diabetes and if so at what age. Associations of diabetes and age at diabetes diagnosis with ANM were estimated using time-dependent Cox regression analyses, with stratification by center and adjustments for age, smoking, reproductive, and known diabetes risk factors including smoking and with age from birth to menopause or censoring as the underlying time scale. Overall, there was no statistically significant lower risk of becoming menopausal among women with diabetes than women with no diabetes; the hazard ratio (HR) was 0.94, with a 95% confidence interval (CI) of 0.89 to 1.01. However, compared with women with no diabetes, women with diabetes before the age of 20 years had an earlier menopause (10-20 years [HR, 1.43; 95% CI, 1.02-2.01] and <10 years [HR, 1.59; 95% CI, 1.03-2.43]), whereas women with diabetes at age 50 years or older had a later menopause (HR, 0.81; 95% CI, 0.70-0.95). No association with ANM was found for diabetes onset between the ages 20 and 50 years. Strengths of the study include its large sample size and the measurement of a broad set of potential confounders. However, there were several limitations. First, results may have been underestimated because of survival bias. Second, the sequence of menopause and diabetes in women with a late age at diabetes is uncertain, as both events occur in a short period, and both diabetes and menopause status were based on self-report, not verified by medical records. Third, no distinction was made between types 1 and 2 diabetes. Although there is no overall association between diabetes and age at menopause, the data suggest that early-onset diabetes may accelerate menopause. The delaying effect of late-onset diabetes on ANM is not in agreement with other studies suggesting the opposite association.

Diabetes and onset of natural menopause: results from the European Prospective Investigation into Cancer and Nutrition.

Do women who have diabetes before menopause have their menopause at an earlier age compared with women without diabetes? Although there was no overall association between diabetes and age at menopause, our study suggests that early-onset diabetes may accelerate menopause. Today, more women of childbearing age are being diagnosed with diabetes, but little is known about the impact of diabetes on reproductive health. We investigated the impact of diabetes on age at natural menopause (ANM) in 258 898 women from the European Prospective Investigation into Cancer and Nutrition (EPIC), enrolled between 1992 and 2000. Determinant and outcome information was obtained through questionnaires. Time-dependent Cox regression analyses were used to estimate the associations of diabetes and age at diabetes diagnosis with ANM, stratified by center and adjusted for age, smoking, reproductive and diabetes risk factors and with age from birth to menopause or censoring as the underlying time scale. Overall, no association between diabetes and ANM was found (hazard ratio (HR) = 0.94; 95% confidence interval (CI) 0.89-1.01). However, women with diabetes before the age of 20 years had an earlier menopause (10-20 years: HR = 1.43; 95% CI 1.02-2.01, <10 years: HR = 1.59; 95% CI 1.03-2.43) compared with non-diabetic women, whereas women with diabetes at age 50 years and older had a later menopause (HR = 0.81; 95% CI 0.70-0.95). None of the other age groups were associated with ANM. Strengths of the study include the large sample size and the broad set of potential confounders measured. However, results may have been underestimated due to survival bias. We cannot be sure about the sequence of the events in women with a late age at diabetes, as both events then occur in a short period. We could not distinguish between type 1 and type 2 diabetes. Based on the literature, an accelerating effect of early-onset diabetes on ANM might be plausible. A delaying effect of late-onset diabetes on ANM has not been reported before, and is not in agreement with recent studies suggesting the opposite association. The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l'Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ) and Federal Ministry of Education and Research (BMMF) (Germany); Ministry of Health and Social Solidarity, Stavros Niarchos Foundation and Hellenic Health Foundation (Greece); Italian Association for Research on Cancer (AIRC) and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); ERC-2009-AdG 232997 and Nordforsk, Nordic Centre of Excellence programme on Food, Nutrition and Health (Norway); Health Research Fund (FIS), Regional Governments of Andalucía, Asturias, Basque Country, Murcia (no. 6236) and Navarra, ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society, Swedish Scientific Council and Regional Government of Skåne and Västerbotten (Sweden); Cancer Research UK, Medical Research Council, Stroke Association, British Heart Foundation, Department of Health, Food Standards Agency, and Wellcome Trust (UK). None of the authors reported a conflict of interest.

Non-Traditional Approaches to Diagnosis and Management of Type-2 Diabetes Mellitus: Point of View

Non-Traditional Approaches to Diagnosis and Management of Type-2 Diabetes Mellitus: Point of View