Over the past three decades, the number of people with diabetes mellitus has more than doubled globally, making it one of the most important public health challenges to all nations. Type 2 diabetes mellitus (T2DM) and prediabetes are increasingly observed among children, adolescents and younger adults. The causes of the epidemic of T2DM are embedded in a very complex group of genetic and epigenetic systems interacting within an equally complex societal framework that determines behavior and environmental influences. This complexity is reflected in the diverse topics discussed in this Review. In the past few years considerable emphasis has been placed on the effect of the intrauterine environment in the epidemic of T2DM, particularly in the early onset of T2DM and obesity. Prevention of T2DM is a 'whole-of-life' task and requires an integrated approach operating from the origin of the disease. Future research is necessary to better understand the potential role of remaining factors, such as genetic predisposition and maternal environment, to help shape prevention programs. The potential effect on global diabetes surveillance of using HbA(1c) rather than glucose values in the diagnosis of T2DM is also discussed.

The worldwide epidemiology of type 2 diabetes mellitus--present and future perspectives

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(14)61375-1.pdf

Cushing's syndrome

The metabolic syndrome is a multiplex risk factor that consists of several risk correlates of metabolic origin. In addition, to dyslipidemia, hypertension, and hyperglycermia, the syndrome carries a prothrombotic state and a proinflammatory state. Persons with the metabolic syndrome are at essentially twice the risk for cardiovascular disease compared with those without the syndrome. It further raises the risk for type 2 diabetes by about 5-fold. Although some investigators favor keeping risk factors separate for purposes of clinical management, others believe that identifying individuals with an aggregation of risk factors provides additional useful information to guide clinical management. In particular it focuses attention on obesity and sedentary life habits that are the root of the syndrome. This review addresses the prevalence of this clustering phenomenon throughout the world. Such seems appropriate because of the increasing prevalence of obesity in almost all countries. The available evidence indicates that in most countries between 20% and 30% of the adult population can be characterized as having the metabolic syndrome. In some populations or segments of the population, the prevalence is even higher. On the other hand, in parts of developing world in which young adults predominate, the prevalence is lower; but with increasing affluence and aging of the population, the prevalence undoubtedly with rise.

Metabolic Syndrome Pandemic

Type 2 diabetes is now epidemic. In the U.S., there has been a 61% increase in incidence between 1990 and 2001 (1). There are currently 1.5 million new cases per year, and the prevalence in 2005 was almost 21 million (2). The epidemic has affected developed and developing countries alike, and the worldwide prevalence of diabetes is projected to increase dramatically by 2025 (3). The increase in type 2 diabetes is related to lifestyle changes that have resulted in overweight, obesity, and decreased physical activity levels. These environmental changes, superimposed on genetic predisposition, increase insulin resistance, which, in concert with progressive β-cell failure, results in rising glycemia in the nondiabetic range. In addition to the risk for diabetes, insulin resistance and impaired insulin secretion are accompanied by a host of major cardiovascular disease (CVD) risk factors including hypertension and dyslipidemia. Further reduction in insulin secretion over time results in increasing glycemia and the development of diabetes, which in turn is associated with the development of microvascular and cardiovascular complications.

The transition from the early metabolic abnormalities that precede diabetes, impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), to diabetes may take many years; however, current estimates indicate that most individuals (perhaps up to 70%) with these pre-diabetic states eventually develop diabetes (4–10). During the pre-diabetic state, the risk of a CVD event is modestly increased (11–22). With the development of diabetes, however, there is a large increase in risk for CVD, as well as for long-term complications affecting the eyes, kidneys, and nervous system. The complications of diabetes, which are the cause of major morbidity and mortality, are related to its duration, chronic level of glycemia, and other risk factors.

Although clinical trials have demonstrated the effectiveness of intensive glycemic and blood pressure control to …

https://care.diabetesjournals.org/content/diacare/30/3/753.full.pdf

Impaired fasting glucose and impaired glucose tolerance: implications for care.

Background—Consumption of soft drinks has been linked to obesity in children and adolescents, but it is unclear whether it increases metabolic risk in middle-aged individuals. Methods and Results—We related the incidence of metabolic syndrome and its components to soft drink consumption in participants in the Framingham Heart Study (6039 person-observations, 3470 in women; mean age 52.9 years) who were free of baseline metabolic syndrome. Metabolic syndrome was defined as the presence of 3o f the following: waist circumference 35 inches (women) or 40 inches (men); fasting blood glucose 100 mg/dL; serum triglycerides 150 mg/dL; blood pressure 135/85 mm Hg; and high-density lipoprotein cholesterol 40 mg/dL (men) or 50 mg/dL (women). Multivariable models included adjustments for age, sex, physical activity, smoking, dietary intake of saturated fat, trans fat, fiber, magnesium, total calories, and glycemic index. Cross-sectionally, individuals consuming 1 soft drink per day had a higher prevalence of metabolic syndrome (odds ratio [OR], 1.48; 95% CI, 1.30 to 1.69) than those consuming 1 drink per day. On follow-up (mean of 4 years), new-onset metabolic syndrome developed in 765 (18.7%) of 4095 participants consuming 1 drink per day and in 474 (22.6%) of 2059 persons consuming 1 soft drink per day. Consumption of 1 soft drink per day was associated with increased odds of developing metabolic syndrome (OR, 1.44; 95% CI, 1.20 to 1.74), obesity (OR, 1.31; 95% CI, 1.02 to 1.68), increased waist circumference (OR, 1.30; 95% CI, 1.09 to 1.56), impaired fasting glucose (OR, 1.25; 95% CI, 1.05 to 1.48), higher blood pressure (OR, 1.18; 95% CI, 0.96 to 1.44), hypertriglyceridemia (OR, 1.25; 95% CI, 1.04 to 1.51), and low high-density lipoprotein cholesterol (OR, 1.32; 95% CI 1.06 to 1.64). Conclusions—In middle-aged adults, soft drink consumption is associated with a higher prevalence and incidence of multiple metabolic risk factors. (Circulation. 2007;116:480-488.)

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Soft Drink Consumption and Risk of Developing Cardiometabolic Risk Factors and the Metabolic Syndrome in Middle-Aged Adults in the Community

Background Irradiation of the pituitary is widely considered the most appropriate treatment for patients with Cushing's disease in whom transsphenoidal microsurgery has been unsuccessful. However, there is little information about the long-term efficacy of this treatment. Methods We used external pituitary radiation to treat 30 adult patients with persistent or recurrent Cushing's disease after unsuccessful transsphenoidal surgery. The mean (±SD) dose of radiation was 50±1 Gy. Pituitary and adrenal function was assessed every six months after radiation therapy. Remission was defined as the regression of symptoms and signs of Cushing's syndrome, normal urinary cortisol excretion, and a low plasma cortisol concentration in the morning after the administration of 1 mg of dexamethasone at midnight. Results Twenty-five patients (83 percent) had remissions during a median follow-up of 42 months (range, 18 to 114). The remissions began 6 to 60 months after radiation therapy, but in most cases (22 patients) remis...

https://www.nejm.org/doi/pdf/10.1056/NEJM199701163360303

The Long-Term Outcome of Pituitary Irradiation after Unsuccessful Transsphenoidal Surgery in Cushing's Disease

OBJECTIVE —To assess the cardiovascular risk profile, the degree of insulin resistance, and β-cell secretion in a cohort of subjects with different categories of impaired glucose regulation (IGR): impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and combined IFG/IGT. RESEARCH DESIGN AND METHODS —We studied 902 nondiabetic subjects between 30 and 80 years of age, recruited from a cross-sectional population-based study in Telde, Gran Canaria Island, Spain. Categories of glucose tolerance were defined according to 2003 modified American Diabetes Association criteria. Risk factors for cardiovascular disease, the presence of the metabolic syndrome, and indirect measures of both insulin resistance and β-cell function were analyzed. RESULTS —A total of 132 (14.6%) participants had isolated IFG, 59 (6.5%) isolated IGT, and 48 (5.3%) combined IFG/IGT. Groups with normal glucose tolerance (NGT) and combined IFG/IGT had, respectively, the most favorable and unfavorable levels of cardiovascular risk factors, metabolic syndrome rates, and measures of insulin resistance. Subjects with IFG and IGT showed an intermediate profile between NGT and IFG/IGT categories. We found no significant differences between IFG and IGT in cardiovascular risk factors, metabolic syndrome prevalence, or insulin resistance. The IFG group exhibited a more impaired insulin secretion than those with IGT or IFG/IGT. CONCLUSIONS —Individuals with IGR, especially those with IFG/IGT, have increased values of cardiovascular risk factors and higher indexes of insulin resistance. Groups with isolated IFG and isolated IGT present similar cardiovascular risk profiles. Subjects with IFG are characterized by more defective β-cell function than other forms of IGR.

https://care.diabetesjournals.org/content/diacare/28/10/2388.full.pdf

Differences in Cardiovascular Risk Factors, Insulin Resistance, and Insulin Secretion in Individuals With Normal Glucose Tolerance and in Subjects With Impaired Glucose Regulation: The Telde Study

OBJECTIVE While inferior petrosal sinus (IPS) sampling correctly diagnoses pituitary-dependent Cushing's syndrome if a significant ratio of plasma ACTH between the IPS and the peripheral blood is demonstrated, little has been said about the significance of a negative ratio in Cushing's disease (e.g. a false-negative result). This study evaluates the results of IPS sampling in patients with Cushing's disease, and compares them with both imaging findings and transsphenoidal examination.

DESIGN The results of IPS sampling were retrospectively compared with both imaging findings and transsphenoidal examination. IPS samples were obtained before and 2, 5 and 10 minutes after intravenous administration of 100 μg of CRH.

PATIENTS Thirty-two patients with Cushing's disease were evaluated. All subsequently underwent transsphenoidal examination of the pituitary gland.

MEASUREMENTS The ratio of the ACTH concentrations at the IPS and in the peripheral blood (IPS : P ratio), and the ratio of the ACTH concentrations between the IPSs (interpetrosal ratio) were calculated. Radiographic evaluation of the pituitary gland was performed with magnetic resonance imaging (MRI, 29 cases) or computed tomography imaging (CT, 3 cases).

RESULTS Transsphenoidal examination of the pituitary gland revealed a microadenoma in 27 cases. Radiological imaging showed a signal compatible with a microadenoma in 22 cases (68.8%), and correctly located the tumour at the side found at surgery in 14 of the 22 cases with positive transsphenoidal findings (MRI 13 cases, CT 1 case, overall 63.6%). Successful bilateral catheterization was accomplished in 30 patients (93.8%). Samples before and after CRH stimulation were drawn in 24 cases. No major complications were observed with the technique. IPS catheterization correctly predicted Cushing's disease (by means of a significant IPS : P ACTH ratio) in 27 of the 30 patients (90%) with basal sampling, and in 23 of the 24 cases with samples drawn before and after CRH administration (95.8%). Taking into account the 12 patients with a lateral microadenoma shown at transsphenoidal examination, IP sinus ACTH ratio was in agreement with the side recorded by the neurosurgeon in 8/12 cases (66.7%). MRi correctly located the tumour in 8/12 patients (66.7%). One patient showed no significant IPS : P ACTH ratio in any set of samples. His MRI showed no sign of a microadenoma. Two years later, another pituitary MRI evaluation showed a midline hypodense signal. The transsphenoidal examination revealed a microadenoma and the post-operative plasma cortisol and urinary free cortisol fell to 293 nmol/l and 100 nmol/24 h, respectively.

CONCLUSIONS Only when a significant IPS : P ACTH ratio is present can Cushing's disease be established by IPS sampling. The absence of a significant IPS : P ACTH ratio does not necessarily imply ectopic secretion of ACTH, nor does it exclude Cushing's disease. The results of lateralization by IPS sampling do not remove the need for a thorough transsphenoidal examination of the contents of the sella turcica.

Petrosal sinus sampling for diagnosis of Cushing's disease: evidence of false negative results

Aims To estimate the prevalence and the determinants of diabetes mellitus and impaired glucose regulation (IGR) in an adult Canarian population.



Methods  Cross-sectional study. One thousand and thirty subjects aged 30–82 years were randomly selected. Participants completed a survey questionnaire and underwent blood pressure measurements, anthropometry, blood samples, and a 75-g standardized oral glucose tolerance test.



Results  The age-standardized prevalence of diabetes was 15.8% (95% confidence interval: 11.8–19.8) in men and 10.6% (7.1–14.1) in women. Total prevalence was 13.2% (11.1–15.2). Among individuals with diabetes, 55.4% of men and 38.2% of women were not previously diagnosed. The age-standardized prevalences of impaired glucose tolerance and impaired fasting glycaemia were 11.4% (9.5–13.4) and 2.8% (1.8–3.8), respectively. In multivariate analyses, age, waist circumference, serum triglycerides, and familial history of diabetes were independently associated with diabetes in both sexes, while a value of C-reactive protein (CRP) ≥ 1 mg/l showed an association with diabetes, but only in men. Age and triglycerides were related to impaired glucose regulation (IGR) in both sexes, waist circumference was related to IGR exclusively in men, and familial diabetes exclusively in women. Statistically significant interactions between gender and both CRP and triglycerides were found with respect to diabetes, and between gender and both waist circumference and triglycerides for IGR.



Conclusions  Compared with the rest of Spain, the prevalence of diabetes is moderately increased in this area of the Canary Islands. Along with other well-established risk factors, CRP was independently associated with diabetes, but only in the male population.

Diabetes mellitus and impaired glucose regulation in the Canary Islands (Spain): prevalence and associated factors in the adult population of Telde, Gran Canaria

Background. Ketoconazole is the most widely used medical treatment for Cushing's syndrome, but, because of its potential to cause birth defects, it is not recommended during pregnancy. Specifically, due to its antiandrogenic effects, ketoconazole entails theoretical risks of interfering with the development of external genitalia in male fetuses.Case. A pregnancy was diagnosed at 13 weeks of gestation in a 26-year-old woman with Cushing's disease under treatment with ketoconazole. The drug was withdrawn and the patient underwent transsphenoidal surgery at 16 weeks of pregnancy. She did not develop postsurgical adrenal insufficiency and was treated with metyrapone during the second and third trimesters of gestation. Partum was induced at 34 weeks of pregnancy. The patient delivered a healthy male infant with normal external genitalia.Conclusion. Treatment with ketoconazole during the critical period of organogenesis did not cause congenital birth defects to the male fetus of a woman with Cushing's disease. ...

Mauro Boronat

Papers

The Long-Term Outcome of Pituitary Irradiation after Unsuccessful Transsphenoidal Surgery in Cushing's Disease

Differences in Cardiovascular Risk Factors, Insulin Resistance, and Insulin Secretion in Individuals With Normal Glucose Tolerance and in Subjects With Impaired Glucose Regulation: The Telde Study

Petrosal sinus sampling for diagnosis of Cushing's disease: evidence of false negative results

Diabetes mellitus and impaired glucose regulation in the Canary Islands (Spain): prevalence and associated factors in the adult population of Telde, Gran Canaria

Successful outcome of pregnancy in a patient with Cushing's disease under treatment with ketoconazole during the first trimester of gestation.