Delta cell death in the islet of Langerhans and the progression from normal glucose tolerance to type 2 diabetes in non-human primates (baboon, Papio hamadryas).

AIMS/HYPOTHESIS: The cellular composition of the islet of Langerhans is essential to ensure its physiological function. Morphophysiological islet abnormalities are present in type 2 diabetes but the relationship between fasting plasma glucose (FPG) and islet cell composition, particularly the role of delta cells, is unknown. We explored these questions in pancreases from baboons (Papio hamadryas) with FPG ranging from normal to type 2 diabetic values. METHODS: We measured the volumes of alpha, beta and delta cells and amyloid in pancreatic islets of 40 baboons (Group 1 [G1]: FPG < 4.44 mmol/l [n = 10]; G2: FPG = 4.44-5.26 mmol/l [n = 9]; G3: FPG = 5.27-6.94 mmol/l [n = 9]; G4: FPG > 6.94 mmol/l [n = 12]) and correlated islet composition with metabolic and hormonal variables. We also performed confocal microscopy including TUNEL, caspase-3, and anti-caspase cleavage product of cytokeratin 18 (M30) immunostaining, electron microscopy, and immuno-electron microscopy with anti-somatostatin antibodies in baboon pancreases. RESULTS: Amyloidosis preceded the decrease in beta cell volume. Alpha cell volume increased ∼ 50% in G3 and G4 (p < 0.05), while delta cell volume decreased in these groups by 31% and 39%, respectively (p < 0.05). In G4, glucagon levels were higher, while insulin and HOMA index of beta cell function were lower than in the other groups. Immunostaining of G4 pancreatic sections with TUNEL, caspase-3 and M30 showed apoptosis of beta and delta cells, which was also confirmed by immuno-electron microscopy with anti-somatostatin antibodies. CONCLUSIONS/INTERPRETATION: In diabetic baboons, changes in islet composition correlate with amyloid deposition, with increased alpha cell and decreased beta and delta cell volume and number due to apoptosis. These data argue for an important role of delta cells in type 2 diabetes.

Effect of linagliptin on glucose metabolism and pancreatic beta cell function in patients with persistent prediabetes after metformin and lifestyle.

The goal of the study was to evaluate the effect of adding linagliptin to metformin and lifestyle on glucose levels and pancreatic ß-cell function in patients with persistent impaired glucose tolerance (IGT) after 12 months of metformin and lifestyle. A single center parallel double-blind randomized clinical trial with 6 months of follow-up was performed in patients with persistent IGT after 12 months of treatment with metformin and lifestyle; patients were randomized to continue with metformin 850 mg twice daily (M group, n = 12) or linagliptin/metformin 2.5/850 mg twice daily (LM group, n = 19). Anthropometric measurements were obtained by standard methods and by bioelectrical impedance; glucose was measured by dry chemistry, insulin by chemiluminescence, and pancreatic ß-cell function was calculated with the disposition index using glucose and insulin values during oral glucose tolerance test (OGTT) and adjusting by insulin sensitivity. The main outcomes were glucose levels during OGTT and pancreatic ß-cell function. Patients in the LM group had a reduction in weight (-1.7 ± 0.6, p < 0.05) and body mass index (BMI, -0.67 ± 0.2, p < 0.05). Glucose levels significantly improved in LM group with a greater reduction in the area under the glucose curve during OGTT (AUCGluc0_120min) as compared to the M group (-4425 ± 871 vs -1116 ± 1104 mg/dl/120 min, p < 0.001). Pancreatic ß-cell function measured with the disposition index, improved only in LM group (2.3 ± 0.23 vs 1.7 ± 0.27, p 0.001); these improvements persisted after controlling for OGTT glucose levels. The differences in pancreatic ß-cell function persisted also after pairing groups for basal AUCGluc0_120min. The addition of linagliptin to patients with persistent IGT after 12 months of treatment with metformin and lifestyle, improved glucose levels during OGTT and pancreatic ß-cell function after 6 months of treatment.Trial registration: Clinicaltrials.gov with the ID number NCT04088461.

Progressive Shifts in the Gut Microbiome Reflect Prediabetes and Diabetes Development in a Treatment-Naive Mexican Cohort.

Type 2 diabetes (T2D) is a global epidemic that affects more than 8% of the world's population and is a leading cause of death in Mexico. Diet and lifestyle are known to contribute to the onset of T2D. However, the role of the gut microbiome in T2D progression remains uncertain. Associations between microbiome composition and diabetes are confounded by medication use, diet, and obesity. Here we present data on a treatment-naive cohort of 405 Mexican individuals across varying stages of T2D severity. Associations between gut bacteria and more than 200 clinical variables revealed a defined set of bacterial genera that were consistent biomarkers of T2D prevalence and risk. Specifically, gradual increases in blood glucose levels, beta cell dysfunction, and the accumulation of measured T2D risk factors were correlated with the relative abundances of four bacterial genera. In a cohort of 25 individuals, T2D treatment-predominantly metformin-reliably returned the microbiome to the normoglycemic community state. Deep clinical characterization allowed us to broadly control for confounding variables, indicating that these microbiome patterns were independent of common T2D comorbidities, like obesity or cardiovascular disease. Our work provides the first solid evidence for a direct link between the gut microbiome and T2D in a critically high-risk population. In particular, we show that increased T2D risk is reflected in gradual changes in the gut microbiome. Whether or not these T2D-associated changes in the gut contribute to the etiology of T2D or its comorbidities remains to be seen.

The combination of linagliptin, metformin and lifestyle modification to prevent type 2 diabetes (PRELLIM). A randomized clinical trial.

BACKGROUND: Prediabetes is a highly prevalent health problem with a high risk of complications and progression to type 2 diabetes (T2D). The goals of this study were to evaluate the effect of the combination of lingaliptin + metformin + lifestyle on glucose tolerance, pancreatic ß-cell function and T2D incidence in patients with prediabetes. METHODS: A single center parallel double-blind randomized clinical trial with 24 months of follow-up in patients with impaired glucose tolerance plus two T2D risk factors which were randomized to linagliptin 5 mg + metformin 1700 mg daily + lifestyle (LM group) or metformin 1700 mg daily + lifestyle (M group). Primary outcomes were regression to normoglycemia and T2D incidence; glucose levels and pancreatic ß-cell function were secondary outcomes. RESULTS: Subjects were screened for eligibility by OGTT and 144 patients with prediabetes were randomized to LM group (n = 74) or M group (n = 70); 52 and 36 participants in the LM group and 52 and 27 participants in the M group, completed the 12 and 24 months of treatment, respectively; average follow-up was 17 ±â€¯6 and 18 ±â€¯7 months in M and LM group, respectively. Glucose levels during OGTT improved more in LM group. OGTT disposition index (DI) improved significantly better during the first months in LM group, increasing from 1·31 (95% CI: 1·14-1·49) to 2·41 (95% CI: 2.10-2.72) and to 2.07 (95% CI: 1.82-2.31) at 6 and 24 months in LM group vs from 1.21 (95% CI: 0.98-1.34) to 1.56 (95% CI: 1.17-1.95) and to 1.72 (95% CI: 1.45-1.98) at 6 and 24 months in M group (p < .05). T2D incidence was higher in M group in comparison to LM group (HR 4.0, 95% CI: 1.24-13.04, p = .020). The probability of achieving normoglycemia was higher in LM group (OR 3.26 CI 95% 1.55-6.84). No major side effects were observed during the study. CONCLUSIONS: The combination of linagliptin, metformin and lifestyle improved significantly glucose metabolism and pancreatic ß-cell function, and reduced T2D incidence in subjects with prediabetes as compared to metformin and lifestyle.

Fibrinogen is associated with silent myocardial ischaemia in type 2 diabetes mellitus.

OBJECTIVE: Because traditional risk factors only partially explain coronary events, it is necessary to search for new ones like fibrinogen which has been related with coronary disease in healthy middle-aged adults. We attempted to determine the impact of fibrinogen on silent myocardial ischaemia (SMI) in diabetic patients. METHODS AND RESULTS: In a cross-sectional study, 134 type 2 diabetes patients with no history of cardiovascular disease were assessed for SMI. A personal history and physical evaluation of each patient was conducted as well as evaluation of cholesterol, glucose, fibrinogen, blood cell counts, glycated haemoglobin, urine albumin quantification, and urinalysis. A modified Bruce test was performed on all study participants to evaluate the presence of SMI. RESULTS: Eleven patients had SMI (8.2%) that was associated with systolic, diastolic and mean blood pressure, hypertension, and fibrinogen. The correlation coefficient was obtained for quintiles of fibrinogen with the percentage of patients with SMI in that quintile (r = 0.97; 95% = 0.66-0.99). Fibrinogen levels were associated with SMI. A receiver-operator curve analysis showed that the cutoff value for fibrinogen to predict SMI was 400 mg/dL (82% sensitivity, 81% specificity). A cutoff value of 306 mg/dL of fibrinogen would rule in the diagnosis of SMI (100% sensitivity, 17% specificity), while fibrinogen cutoff of 682 mg/dL would rule out SMI (100% specificity, 9% sensitivity). CONCLUSIONS: Fibrinogen strongly predicts SMI in diabetic patients and may identify individuals with high cardiovascular risk. Fibrinogen should be evaluated in diabetic patients for a more accurate cardiovascular evaluation.

Linagliptin plus insulin for hyperglycemia immediately after renal transplantation: A comparative study.

AIMS: Post-renal-transplanted patients frequently present hyperglycemia immediately after the procedure. The goal of this work was to evaluate the effect of linagliptin + insulin in post-renal-transplanted patients with hyperglycemia. METHODS: Retrospective comparative study in post-renal transplanted patients with hyperglycemia after transplantation who were treated with linagliptin 5 mg daily plus insulin vs insulin alone for 5 days after renal transplantation with hyperglycemia. Main outcomes were glucose levels, insulin dose and severity of hypoglycemia. RESULTS: There were 14 patients treated with linagliptin + insulin and 14 patients treated only with insulin. Glucose levels and insulin doses were lower in the linagliptin + insulin group in comparison with the insulin alone group, 131.0 ±â€¯15.1 vs 191.1 ±â€¯22.5 mg/dl (7.27 ±â€¯0.84 vs 10.61 ±â€¯1.25 mmol/l) and 37.5 ±â€¯6.3 vs 24.2 ±â€¯6.6 U, respectively (p < 0.05). Hypoglycemia was less severe in the linagliptin + insulin group, 65.1 ±â€¯2.2 vs 54.2 ±â€¯3.3 mg/dl (3.61 ±â€¯0.12 vs 3.00 ±â€¯3.3 ±â€¯0.18 mmol/l), p 0.036. CONCLUSIONS: The combination of linagliptin + insulin provided better glycemic control with a lower insulin dose and less severe hypoglycemia in comparison to insulin alone in patients with hyperglycemia immediately after renal transplantation.

Pancreatic ß-cell dysfunction in normoglycemic patients and risk factors.

AIMS: To evaluate pancreatic ß-cell function (ßf) in patients with normoglycemia (NG) and normal glucose tolerance (NGT) and related risk factors. METHODS: An observational and comparative study in 527 patients with NG and NGT that were divided by quartiles of ßf according to the disposition index derived from OGTT. Anthropometrical, clinical, nutritional, and biochemical variables were measured and associated with ßf. RESULTS: Quartiles of ßf were Q1 = DI < 1.93 n = 131, Q2 = DI 1.93-2.45 n = 134, Q3 = DI 2.46-3.1 n = 133, and Q4 = DI > 3.1 n = 129. There was a progressive reduction in pancreatic ß-cell function and it is negatively correlated with age, weight, BMI, total body fat and visceral fat, waist circumference, total cholesterol, LDL, and triglycerides (p < 0.01). Glucose levels during OGTT had a negative correlation with ßf; the product of fasting glucose by 1-h glucose had the best correlation with ßf (r = 0.611, p < 0.001) and was the best predictor of ßdf (AUC 0.816, CI 95% 0.774-0.857), even better than 1-h glucose (r = 0.581, p < 0.001). Energy, fat, and carbohydrate intake were negatively correlated with ßf (p < 0.05). Glucose levels at 1-h OGTT > 110 mg/dl were positively associated with pancreatic ßdf (OR 6.85, CI 95% 3.86-12.4). In the multivariate analysis, glucose levels during OGTT, fasting insulin, and BMI were the main factors associated with ßf. CONCLUSIONS: A subgroup of patients with NG and NGT may have a loss of 40% of their ßf. Factors related to this ßdf were age, adiposity, glucose during OGTT, and the product of fasting and 1-h glucose, as well as food intake.

Islet amyloid polypeptide response to maximal hyperglycemia and arginine is altered in impaired glucose tolerance and type 2 diabetes mellitus.

AIMS: Pancreatic islet amyloid deposition is a characteristic feature of type 2 diabetes mellitus (T2DM). Islet amyloid polypeptide (IAPP) is co-secreted with insulin, but its secretion profile and relationship to insulin and C-peptide in response to glucose and non-glucose stimuli has not been clearly defined. METHODS: Forty subjects (13 NGT, 12 IGT and 15 T2DM) participated in an OGTT and two-step hyperglycemic (225 and 400 mg/dl) clamp (80 min/step) followed by an IV arginine bolus. Acute insulin (AIR), C-peptide (ACPR) and IAPP (AIAR) responses during each hyperglycemic step and following arginine (AIRArg) were assessed. RESULTS: AIR and ACPR during both hyperglycemic steps and after arginine progressively decreased from NGT to IGT to T2DM. Fasting IAPP concentrations were higher in T2DM compared to NGT and IGT subjects. The acute IAPP0-10 was markedly decreased only in T2DM, while the acute IAPP80-90 response during the second step (80-160 min) of hyperglycemic clamp and in response to arginine was markedly impaired in both IGT and T2DM. The ratio of IAPP/C-peptide during the first (225 mg/dl) and second step (400 mg/dl), and in response to arginine, was decreased in T2DM versus both NGT and IGT (p < 0.01). The acute IAPP0-10 correlated with ACPR0-10 (r = 0.665, p < 0.001) and AIR0-10 (r = 0.543, p < 0.001). CONCLUSIONS: Basal IAPP secretion is higher in T2DM and IGT versus NGT but is reduced in response to hyperglycemia and arginine. The IAPP/C-peptide ratio is reduced with prolonged and more severe hyperglycemia in T2DM individuals. CLINICAL TRIAL REGISTRATION: NCT00845182.

The role of nateglinide and repaglinide, derivatives of meglitinide, in the treatment of type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) is one of the most common chronic diseases worldwide, presenting a great challenge to the public health systems due to high morbidity and mortality, because of frequent micro-/macro-vascular complications. Many treatment options are now available, with different efficacy as well as mechanisms of action to improve deranged glucose metabolism. We review some of the available data on derivatives of meglitinide, namely nateglinide and repaglinide. These two compounds increase insulin secretion by a mechanism similar to the one of sulfonylureas, but with a shorter half-life. Nateglinide and repaglinide, derivatives of meglitinides, have characteristic pharmacodynamic and pharmacokinetic properties that, together with their proposed mechanism of action, make them useful for type 2 diabetes mellitus, especially when used in combination therapy.

New-onset diabetes mellitus: predictive factors and impact on the outcome of patients undergoing liver transplantation.

Liver transplantation (LT) for hepatocellular carcinoma (HCC) is the treatment of choice for patients with tumor characteristics within the Milan criteria associated with Child B or C cirrhosis. LT provides the best cure for both the tumor and the cirrhosis. There have been several emerging reports that new-onset diabetes mellitus (NODM) after transplantation (NODAT) is one of the most negative predictive factors for low survival rate and related co-morbidities. Little is known about the onset of NODM in post-transplant patients and, overall, whether the pathogenesis of NODM differs from that known for the general population. Principally, it is still unknown whether NODAT is related to the primary hepatic disease, the surgical procedures, immunosuppressive treatments, or is it due to the donor liver. This review will focus on the identification of factors, in the setting of LT, which may lead to the development of NODM. Early prevention of these factors may abate the incidence of NODM and positively impact survival rate, and thus ameliorate the worsening of cardiovascular risk factors which usually occur after LT.

Coordinated defects in hepatic long chain fatty acid metabolism and triglyceride accumulation contribute to insulin resistance in non-human primates.

UNLABELLED: Non-alcoholic fatty liver disease (NAFLD) is characterized by accumulation of triglycerides (TG) in hepatocytes, which may also trigger cirrhosis. The mechanisms of NAFLD are not fully understood, but insulin resistance has been proposed as a key determinant. AIMS: To determine the TG content and long chain fatty acyl CoA composition profile in liver from obese non-diabetic insulin resistant (IR) and lean insulin sensitive (IS) baboons in relation with hepatic and peripheral insulin sensitivity. METHODS: Twenty baboons with varying grades of adiposity were studied. Hepatic (liver) and peripheral (mainly muscle) insulin sensitivity was measured with a euglycemic clamp and QUICKI. Liver biopsies were performed at baseline for TG content and LCFA profile by mass spectrometry, and histological analysis. Findings were correlated with clinical and biochemical markers of adiposity and insulin resistance. RESULTS: Obese IR baboons had elevated liver TG content compared to IS. Furthermore, the concentration of unsaturated (LC-UFA) was greater than saturated (LC-SFA) fatty acyl CoA in the liver. Interestingly, LC-FA UFA and SFA correlated with waist, BMI, insulin, NEFA, TG, QUICKI, but not M/I. Histological findings of NAFLD ranging from focal to diffuse hepatic steatosis were found in obese IR baboons. CONCLUSION: Liver TG content is closely related with both hepatic and peripheral IR, whereas liver LC-UFA and LC-SFA are closely related only with hepatic IR in non-human primates. Mechanisms leading to the accumulation of TG, LC-UFA and an altered UFA: LC-SFA ratio may play an important role in the pathophysiology of fatty liver disease in humans.

Association between human papillomavirus in men and their sexual partners and uterine cervical intraepithelial neoplasia.

OBJECTIVES: To determine whether the presence of human papillomavirus (HPV) in men is a risk factor in the development of intraepithelial cervical neoplasia in their sexual partners and to corroborate HPV frequency and type. MATERIALS AND METHODS: A case-control study was carried out in the city of Colima, Mexico, from October 2004 to September 2005. It included the male sexual partners of females presenting with intraepitheleal neoplasia and with negative cervical uterine cytology. The study was approved by the local ethics committee, and participants signed a letter of informed consent. Samples were taken from the penis with a cytobrush and were analyzed by polymerase chain reaction (PCR) with type-specific HPV consensus primers. Statistical analysis was carried out using averages, percentages, and chi-square test for association. RESULTS: Twenty-one patients and 40 controls were analyzed. Eight were excluded due to DNA degradation. Chi-square test was utilized to find association between risk factor (HPV in men) in men whose sexual partners were women with premalignant lesions and normal Papanicolaou test. There was no statistical significance; OR was 2.5, CI was 0.38-16.41, and P = 0.37 (Fisher's exact test). There was no significant difference between the two study groups. Four HPV-positive cases (19%) were obtained from the case group, and two HPV-positive cases (6%) were obtained from the control group. The six positive samples had low-grade virus. There was no association between HPV in men and the cervical intraepitheleal neoplasia of their sexual partners. CONCLUSIONS: In the present study, HPV in men was not found to be a risk factor in the development of cervical uterine lesions. The viruses that were found were low risk. The sample size employed was not large enough to be able to determine any differences between both study groups.