Genetics of macrovascular complications in type 2 diabetes

Type 2 diabetes mellitus (T2DM) is a metabolic disorder that currently affects more than 400 million worldwide and is projected to cause 552 million cases by the year 2030. Long-term vascular complications, such as coronary artery disease, myocardial infarction, stroke, are the leading causes of morbidity and mortality among diabetic patients. The recent advances in genome-wide technologies have given a powerful impetus to the study of risk markers for multifactorial diseases. To date, the role of genetic and epigenetic factors in modulating susceptibility to T2DM and its vascular complications is being successfully studied that provides the accumulation of genomic knowledge. In the future, this will provide an opportunity to reveal the pathogenetic pathways in the development of the disease and allow to predict the macrovascular complications in T2DM patients. This review is focused on the evidence of the role of genetic variants and epigenetic changes in the development of macrovascular pathology in diabetic patients.     

Surgical strategies for type II diabetes

Diabetes mellitus type II (or type 2 diabetes; DM2) has multiple definitions but is generally considered to be a disease marked by insulin resistance and loss of β cell function that develops in adulthood. Today, greater than 90% of patients with diabetes have DM2. When uncontrolled, DM2 may result in comorbidities such as cardiovascular disease, retinopathy, neuropathy, immune system dysfunction, and renal failure. Classically, treatment of type 2 diabetes has included dietary and lifestyle changes. Even with behavior modification and oral hypoglycemics, many patients are unable to maintain glycemic control. With a growing understanding of the hormonal signals involved in the pathogenesis of type 2 diabetes, there has been a shift in the therapeutic approach to this growing epidemic. Bariatric surgery has been shown to decrease the progression and potentially reverse the effects of diabetes in 80% to 90% of patients. In addition, bariatric operations are associated with sustained weight loss in contrast to nonsurgical options. The antidiabetic effect of bariatric operations is likely due to the improvement in the hormonal dysregulation associated with the development of diabetes. Many patients with diabetes, however, have irreparably damaged insulin production capabilities as well. In addition, it is well recognized that transplantation may be required for patients with severe loss of islet cell function. Surgery for type 2 diabetes, via bariatric procedures and transplantation, has become an important treatment modality for patients with advanced disease.     

Leucine metabolism in type II diabetes mellitus

Severe muscle wasting is a well-recognized characteristic of untreated insulin-deficient diabetes mellitus, a condition in which leucine turnover and oxidation are accelerated. To ascertain whether a similar circumstance exists in type II diabetes when insulin is present but with reduced efficacy, we investigated leucine turnover and oxidation in five obese type II diabetic women by tracer infusion of L-[1-13C,15N]leucine in the postabsorptive state both before and after intensive insulin therapy. With conventional treatment, the type II diabetic women received 61 +/- 33 (SD) U/day of insulin, and their fasting plasma glucose averaged 194 +/- 41 (SD) mg/dl. Leucine carbon flux (QC), nitrogen flux (QN), and oxidation (C) averaged 6.4 +/- 1.2, 15.6 +/- 4.6, and 1.4 +/- 0.3 mmol/h, respectively. These values were not different from the respective values of 6.6 +/- 1.3, 17.0 +/- 8.3, and 1.0 +/- 0.2 mmol/h in matched obese nondiabetic controls, suggesting that leucine metabolism is not altered in insulin-treated type II diabetics. After a week of intensive insulin therapy in which the same diabetic subjects received 94 +/- 36 U/day of insulin, postabsorptive plasma glucose declined to 117 +/- 26 mg/dl. Leucine QC (6.2 +/- 1.0), QN (14.8 +/- 3.7), and C (1.5 +/- 0.5 mmol/h) were unaltered by the increased insulin therapy. Thus, obese type II diabetics had normal leucine kinetics but were hyperglycemic while receiving conventional insulin therapy. Additional intensive insulin therapy in these diabetic subjects improved plasma glucose but did not alter leucine kinetics.(ABSTRACT TRUNCATED AT 250 WORDS)     

Noninsulin-dependent, type II diabetes mellitus-related dermatoses: part II

Cutaneous complications of noninsulin-dependent, type II diabetes mellitus are reviewed, including diabetic dermopathy, necrobiosis lipoidica diabeticorum, diabetic bullae (bullosis diabeticorum), certain acquired perforating dermatoses, diabetic thick skin, scleredema adultorum, Dupuytren's contractures, certain xanthomas, carotenoderma, rubeosis faciei, and acanthosis nigricans.     

Toxic stress,inflammation and symptomatology of chronic complications in diabetes

Diabetes affects at least 382 million people worldwide and the incidence is expected to reach 592 million by 2035.The incidence of diabetes in youth is skyrocketing as evidenced by a 21% increase in type 1 diabetes and a 30.5% increase in type 2 diabetes in the United States between 2001 and 2009.The effects of toxic stress,the culmination of biological and environmental interactions,on the development of diabetes complications is gaining attention.Stress impacts the hypothalamus-pituitaryadrenal axis and contributes to inflammation,a keybiological contributor to the pathogenesis of diabetes and its associated complications.This review provides an overview of common diabetic complications such as neuropathy,cognitive decline,depression,nephropathy and cardiovascular disease.The review also provides a discussion of the role of inflammation and stress in the development and progression of chronic complications of diabetes,associated symptomatology and importance of early identification of symptoms of depression,fatigue,exercise intolerance and pain.     

Renal hemodynamics in recent-onset type II diabetes.

Glomerular hyperfiltration is thought to play an important role in the genesis of diabetic nephropathy. While hyperfiltration is well documented in early type I diabetes, the evidence for hyperfiltration in type II diabetes is conflicting. We investigated 16 nonproteinuric patients with recently diagnosed type II diabetes. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured as inulin clearance (CIN) and p-aminohippuric acid clearance (CPAH) using a constant infusion technique. Lean body mass was measured by densitometry (weighing under water). Renal hemodynamics were also measured in 31 healthy volunteers and six obese nondiabetic individuals. Median GFR in diabetics (133 mL/min/1.73 m2; range, 95 to 165) was significantly (P < 0.01) higher than in obese nondiabetic controls (median, 118; range, 95 to 139). Elevated GFR (ie, > 95th percentile of nonobese healthy controls) was found in 44% of patients. When GFR was factored for lean body mass, it was elevated in 50%. GFR did not correlate with fasting glucose, hemoglobin A1C (HbA1C), insulin-like growth factors, IGF-1 and IGF-2, or somatomedin-binding protein (SMBP). The findings document that hyperfiltration is common in recent-onset type II diabetics.     

Association between mannose-binding lectin and vascular complications in type 1 diabetes

Complement activation and inflammation have been suggested in the pathogenesis of diabetic vascular lesions. We investigated serum mannose-binding lectin (MBL) levels and polymorphisms in the MBL gene in type 1 diabetic patients with and without diabetic nephropathy and associated macrovascular complications. Polymorphisms in the MBL gene and serum MBL levels were determined in 199 type 1 diabetic patients with overt nephropathy and 192 type 1 diabetic patients with persistent normoalbuminuria matched for age, sex, and duration of diabetes, as well as in 100 healthy control subjects. The frequencies of high- and low-expression MBL genotypes were similar in patients with type 1 diabetic and healthy control subjects. High MBL genotypes were significantly more frequent in diabetic patients with nephropathy than in the normoalbuminuric group, and the risk of having nephropathy given a high MBL genotype assessed by odds ratio (OR) was 1.52 (1.02-2.27, P = 0.04). Median serum MBL concentrations were significantly higher in patients with nephropathy than in patients with normoalbuminuria: 2,306 microg/l (interquartile range [IQR] 753-4,867 microg/l) vs. 1,491 microg/l (577-2,944 microg/l), P = 0.0003. In addition, even when comparing patients with identical genotypes, serum MBL levels were higher in the nephropathy group than in the normoalbuminuric group. Patients with a history of cardiovascular disease had significantly elevated MBL levels independent of nephropathy status (3,178 microg/l [IQR 636-5,231 microg/l] vs. 1,741 microg/l [656-3,149 microg/l], P = 0.02). The differences in MBL levels between patients with and without vascular complications were driven primarily by pronounced differences among carriers of high MBL genotypes (P < 0.0001). Our findings suggest that MBL may be involved in the pathogenesis of micro- and macrovascular complications in type 1 diabetes, and that determination of MBL status might be used to identify patients at increased risk of developing these complications.     

Insulin sensitivity and complications in type 1 diabetes: New insights

Despite improvements in glucose, lipids and bloodpressure control, vascular complications remain the most important cause of morbidity and mortality in patients with type 1 diabetes. For that reason, there is a need to identify additional risk factors to utilize in clinical practice or translate to novel therapies to prevent vascular complications. Reduced insulin sensitivity is an increasingly recognized component of type 1 diabetes that has been linked with the development and progression of both micro- and macrovascular complications. Adolescents and adults with type 1 diabetes have reduced insulin sensitivity, even when compared to their non-diabetic counterparts of similar adiposity, serum triglycerides, high-density lipoprotein cholesterol, level of habitual physical activity, and in adolescents, pubertal stage. Reduced insulin sensitivity is thought to contribute both to the initiation and progression of macro- and microvascular complications in type 1 diabetes. There are currently clinical trials underway examining the benefits of improving insulin sensitivity with regards to vascular complications in type 1 diabetes. Reduced insulin sensitivity is an increasingly recognized component of type 1 diabetes, is implicated in the pathogenesis of vascular complications and is potentially an important therapeutic target to prevent vascular complications. In this review, we will focus on the pathophysiologic contribution of insulin sensitivity to vascular complications and summarize related ongoing clinical trials.     

The impact of youth-onset type 2 diabetes on postoperative wound healing complications

Youth-onset type 2 diabetes mellitus is associated with a more rapid decline in β cells, and earlier onset of medical complications compared to adult-onset diabetes. However, its impact on surgical wounds remains less clear. Therefore, this study aimed to determine whether youth-onset diabetes is a risk factor for wound healing complications in the 30-day postoperative period. To do so, the National Surgical Quality Improvement Program Database years 2012–2019 was analysed. Patients aged 18–24 with non-insulin-dependent diabetes were included. Outcomes assessed included wound infections, wound dehiscence, readmissions, and reoperation. Univariate analysis identified differences between the diabetic and non-diabetic cohorts after which, multivariate logistic regression was employed to control for potential confounding. Analysis included 1589 diabetic and 196,902 non-diabetic patients ages 18–24. The diabetic cohort exhibited a higher proportion of female (83.8% vs. 55.2%, p < 0.001), non-white (22.7% vs. 19.5%, p = 0.001), and Hispanic patients (16.2% vs. 13.6%, p = 0.002). Diabetic patients were less likely to have dirty or contaminated wounds (16.2% vs. 25.2%, p < 0.001); however had increased rates of superficial surgical site infections (SSSIs; 2.0% vs. 0.8%, p < 0.001) and readmission (4.0% vs. 3.0%, p = 0.026). After regression, diabetes remained a significant positive predictor of SSSI (odds ratio: 1.546, p = 0.022); however, it no longer significantly predicted 30-day readmission. Overall, this analysis of a large multicentre surgical outcomes database found that when compared to non-diabetics, youth-onset diabetic patients exhibited a higher proportion of SSSIs in the 30-day postoperative period. These infections were found, despite the diabetic cohort exhibiting lower rates of wound contamination. After controlling for confounding variables, youth-onset diabetes remained a significant predictor of SSSI. Clinically, prevention and treatment of diabetes along with judicious wound care is recommended.     

Renal sensitivity to angiotensin II in type 1 diabetes

The role of the renin angiotensin system for the regulation of kidney function in diabetes mellitus is uncertain. Results from studies in diabetic animals suggest that a reduced activity in this system contributes to the renal hyperperfusion and hyperfiltration in diabetes. The renal sensitivity to angiotensin II in diabetic patients is also unknown. Changes in renal hemodynamics were measured after infusion of two low doses of angiotensin II in ten young type 1 diabetic patients without complications and in ten healthy controls. The renin and angiotensin II levels were found to be the same in both groups. The baseline glomerular filtration rate was higher in the diabetics. During the highest angiotensin II dose, the 51Cr-EDTA and PAH clearance decreased 14 +/- 15 and 157 +/- 118 ml/min in the diabetics and 14 +/- 15 and 146 +/- 109 in the controls respectively. The changes in blood pressure and renal vascular resistance or sodium excretion did not differ between the groups. A malfunction of the renin angiotensin system is thus unlikely as a cause of the glomerular hyperfiltration in type 1 diabetes.     

Decreased survival of islet allografts in rats with advanced chronic complications of diabetes

Successful islet transplantation has been possible in experimental animals in contrast to humans. One difference between animal models of diabetes and human islet transplantation is the presence of advanced chronic complications in humans. Even longer-term follow-up of islet transplantation in humans according to the Edmonton protocol suggests that advanced chronic complications may adversely affect allograft survival with the glucocorticoid-free immunosuppressive regimen as well. We developed a rat model of chronic complications of diabetes and compared islet allograft survival in rats with advanced chronic complications to age-matched control rats with acute onset diabetes. Islets were transplanted at either the renal supcapsular, intrahepatic, or intramuscular location. The survival of islet allografts in rats with chronic complications was decreased at all sites compared with the age-matched controls. The best survival in the rats with advanced chronic complications occurred at the renal subcapsular site. Blood sugar measurements indicated impaired glucose tolerance in most of the rats with chronic complications and surviving renal subcapsular islet allograft. Histological and gross examination of the surviving renal subcapsular islet allografts indicated disordered angiogenesis in the rats with chronic complications. Rats with successful intrahepatic islet allografts and the respective age-matched controls had comparable blood sugars. Survival of islet allografts at the intramuscular site was poor in rats with chronic complications or acute onset diabetes. We conclude that the structural or metabolic abnormalities associated with chronic poor control of diabetes impair islet allograft survival and function. This should be considered as a possible explanation for failure of islet allograft survival in human islet transplantation.     

Rodent models of nephropathy associated with type II diabetes.

End-stage renal disease from diabetic nephropathy, mainly due to type II diabetes, is an increasing problem in Western countries. The pathogenesis of diabetic nephropathy is still incompletely understood and much of the experimental insight has been obtained from insulinopenic animal models, resembling type I diabetes. This review therefore aims to describe available rodent models of nephropathy associated with type II diabetes. The review focusses on the metabolic as well as renal functional and structural changes. The usefulness of these rodent models to study renal involvement in type II diabetes is discussed with particular emphasis on confounding factors such as hyperlipidemia, hypertension, immunologic abnormalities, urogenital structural abnormalities and other associated pathological conditions. In addition recent observations on two rat strains, the obese Zucker (fatty) and Goto Kakizaki (GK) rat, are discussed in detail.