Ultrastructure of islet microcirculation, pericytes and the islet exocrine interface in the HIP rat model of diabetes.

CONTEXT: The transgenic human islet amyloid polypeptide (HIP) rat model of type 2 diabetes mellitus (T2DM) parallels the functional and structural changes in human islets with T2DM. OBJECTIVE: The transmission electron microscope (TEM) was utilized to observe the ultrastructural changes in islet microcirculation. METHODS: Pancreatic tissue from male Sprague Dawley rats (2, 4, 8, 14 months) were used as controls (SDC) and compared to the 2-, 4-, 8- and 14-month-old HIP rat models. RESULTS: The 2-month-old HIP model demonstrated no islet or microcirculation remodeling changes when compared to the SDC models. The 4-month-old HIP model demonstrated significant pericapillary amyloid deposition and diminution of pericyte foot processes as compared to the SDC models. The 8-month-old model demonstrated extensive islet amyloid deposition associated with pericyte and beta-cell apoptosis when compared with SDC. The 14-month-old HIP model demonstrated a marked reduction of beta-cells and intra-islet capillaries with near complete replacement of islets by amyloidoses. Increased cellularity in the region of the islet exocrine interface was noted in the 4- to 14-month-old HIP models as compared to SDC. In contrast to intra-islet capillary rarefaction there was noticeable angiogenesis in the islet exocrine interface. Pericytes seemed to be closely associated with collagenosis, intra-islet adipogenesis and angiogenesis in the islet exocrine interface. CONCLUSION: The above novel findings regarding the microcirculation and pericytes could assist researchers and clinicians in a better morphological understanding of T2DM and lead to new strategies for prevention and treatment of T2DM.

Longitudinal ultrastructure study of islet amyloid in the HIP rat model of type 2 diabetes mellitus.

In 2004, the human islet amyloid polypeptide (HIP) rat model was created by transfecting the Sprague-Dawley rat with the human islet amyloid polypeptide (hIAPP)-amylin gene. The objective of this study is to utilize the transmission electron microscope to study the longitudinal cellular and extracellular morphological changes within the islets of this model at 4, 8, and 14 months of age. It has been previously demonstrated that the 2-, 5-, and 10-month HIP models have no diabetes, impaired fasting glucose, and diabetes, respectively. The 4-month HIP model (FBS 123 mg/dl) demonstrated an abundance of beta-cells and insulin secretory granules with significant pericapillary and inter-beta-cell islet amyloid deposition. The 8-month model (FBS 187 mg/dl) demonstrated extensive islet amyloid deposition and marked changes of beta-cell apoptosis. The 14-month-old model (FBS 244 mg/dl) demonstrated islet and beta-cell atrophy with even greater amounts of extracellular islet amyloid compared to the 4-month-old and 8-month-old models. Functional beta cells were sparse and were associated with intra islet adipose deposition. These findings of ultrastructure cellular and extracellular morphological longitudinal remodeling changes in this novel animal model of type 2 diabetes may provide investigators with a better understanding regarding the role of islet amyloid in human islet.

Proximal tubule microvilli remodeling and albuminuria in the Ren2 transgenic rat.

TG(mRen2)27 (Ren2) transgenic rats overexpress the mouse renin gene, with subsequent elevated tissue ANG II, hypertension, and nephropathy. The proximal tubule cell (PTC) is responsible for the reabsorption of 5-8 g of glomerular filtered albumin each day. Excess filtered albumin may contribute to PTC damage and tubulointerstitial disease. This investigation examined the role of ANG II-induced oxidative stress in PTC structural remodeling: whether such changes could be modified with in vivo treatment with ANG type 1 receptor (AT(1)R) blockade (valsartan) or SOD/catalase mimetic (tempol). Male Ren2 (6-7 wk old) and age-matched Sprague-Dawley rats were treated with valsartan (30 mg/kg), tempol (1 mmol/l), or placebo for 3 wk. Systolic blood pressure, albuminuria, N-acetyl-beta-D-glucosaminidase, and kidney tissue malondialdehyde (MDA) were measured, and x60,000 transmission electron microscopy images were used to assess PTC microvilli structure. There were significant differences in systolic blood pressure, albuminuria, lipid peroxidation (MDA and nitrotyrosine staining), and PTC structure in Ren2 vs. Sprague-Dawley rats (each P < 0.05). Increased mean diameter of PTC microvilli in the placebo-treated Ren2 rats (P < 0.05) correlated strongly with albuminuria (r(2) = 0.83) and moderately with MDA (r(2) = 0.49), and there was an increase in the ratio of abnormal forms of microvilli in placebo-treated Ren2 rats compared with Sprague-Dawley control rats (P < 0.05). AT(1)R blockade, but not tempol treatment, abrogated albuminuria and N-acetyl-beta-d-glucosaminidase; both therapies corrected abnormalities in oxidative stress and PTC microvilli remodeling. These data indicate that PTC structural damage in the Ren2 rat is related to the oxidative stress response to ANG II and/or albuminuria.

The role of beta-cell dysfunction in the cardiometabolic syndrome.

The regulation of blood glucose levels involves a finely tuned relationship between insulin sensitivity, hepatic glucose output, and production of insulin. The cardiometabolic syndrome includes in its definition criteria a disturbance of normal glucose tolerance and implies development of both insulin resistance and beta-cell dysfunction. There is now abundant evidence pointing toward a central role of dysregulation of the beta-cell function and mass in the development of impaired glucose tolerance. Mechanisms implicated in beta-cell dysfunction include genetic abnormalities, prenatal and early postnatal insults, and environmental events along with obesity, dyslipidemia-lipotoxicity, glucotoxicity, oxidative stress, chronic low-grade inflammation, amyloid deposition, and activation of the local renin-angiotensin system. Novel therapeutic characteristics of known medications such as metformin, thiazolidinediones, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and novel medications such as exendin-4 promise encouraging possibilities to battle against the cardiometabolic syndrome and the future development of cardiovascular disease.

High cardiovascular risk in patients with diabetes and the cardiometabolic syndrome: mandate for statin therapy.

Diabetes mellitus confers a high risk of cardiovascular morbidity and mortality and requires aggressive management of all cardiovascular risk factors, including diabetic dyslipidemia. Although levels of low-density lipoprotein cholesterol are often normal or only slightly elevated in persons with diabetes, lipid-altering therapy with statins has been shown in large, randomized, controlled trials to decrease the risk of cardiovascular complications in this patient population. A target low-density lipoprotein cholesterol level of <70 mg/dL is now a therapeutic option in patients at very high risk for coronary heart disease, including patients with diabetes. Diabetes is also a leading cause of end-stage renal disease. In addition to their lipid-modifying effects, statins have been shown to slow the progression of diabetic nephropathy and potentially exert other renoprotective effects; these benefits, however, remain to be confirmed in clinical trials.

Insights into the emerging cardiometabolic prevention and management of diabetes mellitus.

Cardiovascular disease (CVD) and Type 2 diabetes mellitus (DM2), once conceived as different entities, share common origins and pathways. Increased activity of the renin-angiotensin-aldosterone-system, insulin resistance, chronic low-grade inflammation and oxidative stress collectively contribute to endothelial dysfunction and atherosclerosis, which manifest clinically as CVD. Nowadays, it is possible to identify and intervene in high-risk populations even before the clinical diagnosis of DM2. The control of dietary patterns and increased physical activity is completely feasible, as well as the management of hypertension and dyslipidaemia. Pharmacological interventions targeted at blocking renin-angiotensin-aldosterone-system and sensitising to insulin have a role in the prevention of DM2 and CVD, and are avidly explored worldwide. In the near future, ongoing trials should provide data that will allow us to better treat patients with the cardiometabolic syndrome and diabetes in order to reduce CVD morbidity and mortality.