Type 2 diabetes mellitus is characterized by insulin resistance and failure of pancreatic beta-cells producing insulin. Autophagy plays a crucial role in cellular homeostasis through degradation and recycling of organelles such as mitochondria or endoplasmic reticulum (ER). Here we discussed the role of beta-cell autophagy in development of diabetes, based on our own studies using mice with beta-cell-specific deletion of Atg7 (autophagy-related 7), an important autophagy gene, and studies by others. beta-cell-specific Atg7-null mice showed reduction in beta-cell mass and pancreatic insulin content. Insulin secretory function ex vivo was also impaired, which might be related to organelle dysfunction associated with autophagy deficiency. As a result, beta-cell-specific Atg7-null mice showed hypoinsulinemia and hyperglycemia. However, diabetes never developed in those mice. Obesity and/or lipid are physiological ER stresses that can precipitate beta-cell dysfunction. Our recent studies showed that beta-cell-specific Atg7-null mice, when bred with ob/ob mice, indeed become diabetic. Thus, autophagy deficiency in beta-cells could be a precipitating factor in the progression from obesity to diabetes due to inappropriate response to obesity-induced ER stress.
Animals ; Autophagy/genetics/*physiology ; Diabetes Mellitus/genetics/*metabolism ; Endoplasmic Reticulum Stress/genetics/*physiology ; Humans ; Insulin-Secreting Cells/*metabolism

Adipokines, the bioactive factors derived mainly from adipocytes, regulate pancreatic beta-cell function including insulin secretion, gene expression and apoptosis. In this review, we propose that adipokines influence beta-cell function through three interdependent pathways. The first is through regulating lipid and glucose metabolism in beta-cells. The second implicates the change of ion channel opening and closing in beta-cells. The third pathway is via the modification of insulin sensitivity of beta-cells. The endocrine function of adipocytes is dynamic, and the secretion of various adipokines changes under different metabolic conditions. During the progression from the normal state to obesity and to type 2 diabetes, adipokines contribute to the occurrence and development of beta-cell dysfunction in type 2 diabetes.
Adipocytes ; physiology ; Adiponectin ; physiology ; Animals ; Diabetes Mellitus, Type 2 ; physiopathology ; Glucose ; metabolism ; Humans ; Insulin ; pharmacology ; Insulin-Secreting Cells ; physiology ; Leptin ; physiology ; Lipid Metabolism

Epidermal growth factor receptor (EGFR) cell signaling plays a central role in beta-cell mass/function regulation, and provides a new strategy for the treatment of diabetes, but its mechanisms of action remain poorly understood. In developmental biology, pancreatic islet development is impaired in lacking EGFR of mice. The attenuation of EGFR signaling in the islets leads to markedly reduced beta-cell proliferation. EGFR ligands BTC can increase proliferation and neogenesis. In this article EGFR and their ligands in the pancreas, EGFR cell signaling, and EGFR effects in pancreatic beta-cell mass/function regulation were reviewed.
Betacellulin ; Humans ; Insulin-Secreting Cells ; metabolism ; Intercellular Signaling Peptides and Proteins ; metabolism ; Ligands ; Receptor, Epidermal Growth Factor ; metabolism ; Signal Transduction ; physiology

BACKGROUNDAbnormal insulin secretion of pancreatic beta cells is now regarded as the more primary defect than the insulin function in the etiology of type 2 diabetes. Previous studies found impaired mitochondrial function and impaired Ca(2+) influx in beta cells in diabetic patients and animal models, suggesting a role for these processes in proper insulin secretion. The aim of this study was to investigate the detailed relationship of mitochondrial function, Ca(2+) influx, and defective insulin secretion.

METHODSWe investigated mitochondrial function and morphology in pancreatic beta cell of diabetic KK-Ay mice and C57BL/6J mice. Two types of Ca(2+) channel activities, L-type and store-operated Ca(2+) (SOC), were evaluated using whole-cell patch-clamp recording. The glucose induced Ca(2+) influx was measured by a non-invasive micro-test technique (NMT).

RESULTSMitochondria in KK-Ay mice pancreatic beta cells were swollen with disordered cristae, and mitochondrial function decreased compared with C57BL/6J mice. Ca(2+) channel activity was increased and glucose induced Ca(2+) influx was impaired, but could be recovered by genipin.

CONCLUSIONDefective mitochondrial function in diabetic mice pancreatic beta cells is a key cause of abnormal insulin secretion by altering Ca(2+) influx, but not via Ca(2+) channel activity.

Animals ; Calcium ; metabolism ; Diabetes Mellitus ; metabolism ; physiopathology ; Electrophysiology ; Insulin ; secretion ; Insulin-Secreting Cells ; metabolism ; Male ; Membrane Potential, Mitochondrial ; physiology ; Mice ; Mice, Inbred C57BL ; Mitochondria ; metabolism

Low birth weight is associated with insulin resistance and type 2 diabetes in adults. The fetal programming hypothesis has shown that insulin resistance and its associated metabolic disturbances result from a poor gestational environment, for which low birth weight is a surrogate. An at-home questionnaire survey was performed on 660 middle school students (12-15 years) in Seoul, Korea, and 152 cases were randomly selected based on their birth weight. Subjects were divided into three groups according to birth weight. We recorded their birth weight and measured their current anthropometric data, blood pressure, lipid profile, HOMA-IR, and HOMA-beta, and compared these parameters among the groups. The relation of birth weight to physiological characteristics in adolescence was examined. Systolic blood pressure, lipid profiles, and fasting plasma glucose, HOMA-beta were not significantly different among the groups, but diastolic blood pressure was lower in the third tertile. Insulin, C-peptide, and HOMA-IR were higher in the lower birth weight tertile. After adjustment for confounding factors, birth weight was inversely related to diastolic blood pressure, insulin, C-peptide, and HOMA-IR. We conclude that low birth weight may predict the risk of the insulin resistance and its progression over age, and that adequate gestational nutrition is therefore necessary to prevent low birth weight.
Male ; Korea/epidemiology ; Insulin-Secreting Cells/physiology ; *Insulin Resistance ; Insulin/blood ; Hyperinsulinism/epidemiology/etiology/metabolism ; Humans ; Female ; Child ; C-Peptide/blood ; Blood Pressure ; *Birth Weight ; Adolescent

Non-coding RNA is a kind of non-coding protein RNA which is widely present in most of the organisms. Non-coding RNA plays key roles in the embryonic development,cell fate determination,and growth control in the living organisms. MicroRNA and long non-coding RNA involve in differentiation of endocrine cell,insulin gene expression and secretion,and insulin resistance,which are closely associated with diabetes.
Cell Differentiation ; Diabetes Mellitus ; Gene Expression ; physiology ; Gene Expression Profiling ; Gene Expression Regulation, Developmental ; Humans ; Insulin ; Insulin-Secreting Cells ; Islets of Langerhans ; growth & development ; metabolism ; MicroRNAs ; RNA, Untranslated ; metabolism

BACKGROUNDIncreasingly, evidence from population, clinic-based and laboratory studies supports an independent association between obstructive sleep apnea syndrome (OSAS) and an increased risk of type 2 diabetes; however, this observation has yet to be replicated in China and the potential mechanisms that link these two conditions are not clear.

METHODSA total of 179 Han Chinese subjects were enrolled in this study. All subjects underwent polysomnography, the oral glucose tolerance-insulin releasing test (OGTT-IRT) and serum HbA(1)c measurement. Indexes including homeostasis model assessment-IR (HOMA-IR), Matsuda index, HOMA-β, early phase insulinogenic index (ΔI(30)/ΔG(30)), AUC-I(180) and oral disposition index (DIo) were calculated for the assessment of insulin resistance and pancreatic β-cell function.

RESULTSBased on OGTT, 25.4%, 44.6% and 54.5% subjects were diagnosed having glucose metabolic disorders respectively in control, mild to moderate and severe OSAS groups (P < 0.05). Serum HbA(1)c levels were highest in subjects with severe OSAS (P < 0.05). In contrast, compared with normal subjects, HOMA-β, ΔI(30)/Δ(G30) and DIO were lower in severe OSAS group (P < 0.05). In stepwise multiple linear regressions, 0-min glucose and HbA(1)c were positively correlated with the percentage of total sleep time below an oxyhemoglobin saturation of 90% (T90) (Beta = 0.215 and 0.368, P < 0.05); 30-min and 60-min glucose was negatively correlated with the lowest SpOO(2) (LSpO(2)) (Beta = -0.214 and -0.241, P < 0.05). HOMA-β and DI(O) were negatively correlated with T90 (Beta = -0.153 and -0.169, P < 0.05) while body mass index (BMI) was the only determinant of HOMA-IR and Matsuda index.

CONCLUSIONSOSAS is associated with impairment in glucose tolerance and pancreatic β-cell function in Han Chinese subjects while insulin sensitivity is mainly determined by obesity.

Adolescent ; Adult ; Aged ; Female ; Glucose ; metabolism ; Glucose Tolerance Test ; Glycated Hemoglobin A ; analysis ; Humans ; Insulin Resistance ; Insulin-Secreting Cells ; physiology ; Male ; Middle Aged ; Polysomnography ; Sleep Apnea, Obstructive ; metabolism

OBJECTIVETo investigate the effect of the intrauterine environment on pancreas ghrelin and L-type calcium channels of islet like cell clusters (ICCs) in neonatal rats.

METHODSDifferent birth weight neonatal rat models were established. The samples of entire pancreas or ICCs were collected at the first day after birth. Ghrelin, Cav1.2, Cav1.3 mRNAs and proteins were determined using real-time RT-PCR and immunohistochemistry respectively.

RESULTThe real-time RT-PCR revealed that ghrelin mRNA in SGA group were significantly higher than that of the AGA group (P <0.05). Cav1.2 mRNA of SGA group and LGA group was significantly lower than that of the AGA group; Cav1.3 mRNA of SGA group was significantly lower than that of the AGA group (P <0.05). The results of integral OD value of immunohistochemistry were consistent with those of real-time RT-PCR.

CONCLUSIONIntrauterine nutritional status may affect pancreatic endocrine cells differentiation and maturity, resulting in the difference of expression ghrelin and calcium channels in ICCs.

Animals ; Animals, Newborn ; Birth Weight ; physiology ; Calcium Channels, L-Type ; metabolism ; Fetal Development ; Ghrelin ; metabolism ; Insulin-Secreting Cells ; metabolism ; RNA, Messenger ; metabolism ; Rats ; Rats, Sprague-Dawley

The influence of β-cell function on cardiovascular autonomic neuropathy (CAN), an important diabetes-related complication, is still unclear. In this study, we aimed to investigate the association between residual β-cell function and CAN in patients newly diagnosed with type 2 diabetes. We enrolled 90 newly-diagnosed type 2 diabetic patients and 37 participants with normal glucose tolerance as controls. The patients were divided into a CAN+ group (diabetic patients with CAN, n = 20) and a CAN- group (diabetic patients without CAN, n = 70) according to the standard Ewing battery of tests. Fasting and postprandial plasma glucose, insulin, and C-peptide were measured. Homeostasis model assessment-beta cells (HOMA-B) and HOMA-insulin resistance (IR) were calculated. The prevalence of CAN in this population was 22.2%. Compared with the CAN- group, the CAN+ group had significantly lower fasting plasma insulin (6.60 ± 4.39 vs 10.45 ± 7.82 μ/L, P = 0.029), fasting C-peptide (0.51 ± 0.20 vs 0.82 ± 0.51 nmol/L, P = 0.004), and HOMA-B (21.44 ± 17.06 vs 44.17 ± 38.49, P = 0.002). Fasting C-peptide was correlated with the Valsalva ratio (r = 0.24, P = 0.043) and the 30:15 test (r = 0.26, P = 0.023). Further analysis showed that fasting C-peptide (OR: 0.041, 95% CI 0.003-0.501, P = 0.012) and HOMA-B (OR: 0.965, 95% CI 0.934-0.996, P = 0.028) were independently associated with cardiovascular autonomic nerve function in this population. The patients with fasting C-peptide values < 0.67 nmol/L were more likely to have CAN than those with C-peptide levels ≥0.67 nmol/L (OR: 6.00, 95% CI 1.815-19.830, P = 0.003). A high prevalence of CAN was found in patients with newly-diagnosed type 2 diabetes. Decreased β-cell function was closely associated with CAN in this population.
Adult ; Asian Continental Ancestry Group ; Blood Glucose ; analysis ; Diabetes Mellitus, Type 2 ; complications ; metabolism ; Diabetic Neuropathies ; etiology ; Fasting ; physiology ; Female ; Glucose ; metabolism ; Humans ; Insulin ; metabolism ; Insulin Resistance ; physiology ; Insulin-Secreting Cells ; metabolism ; Male ; Middle Aged

OBJECTIVETo evaluate the age-dependent alteration of insulin and ghrelin expression in the pancreatic islets of intrauterine growth-retarded (IUGR) rats during development and to identify the role of ghrelin in insulin resistance induced by IUGR.

METHODSNeonatal SD rats were divided into normal birth weight group (N group) and intrauterine growth-retarded group (I group). Plasma glucose, ghrelin and serum insulin were analyzed at day 1, 3, 7 and 10 and at week 2, 3, 4,8 and 12 after birth.Entire pancreas samples were collected for determination of ghrelin and insulin mRNA. Immunohistochemical double-staining and confocal microscopy was performed on rat pancreas.

RESULTPlasma insulin levels of I group were lower than those of N group at day 1, 3 and 7 (P <0.05). The homeostasis model assessment-insulin resistance index (HOMA-IR) of I group was higher than that of N group at day 1, 3 and 7 (P<0.05). Plasma glucose levels, insulin, HOMA-IR and ghrelin concentrations decreased in an age-dependent manner (F = 4.12 to approximately 125.97, P <0.001) in both groups. Plasma ghrelin level was correlated with HOMA-IR in I group(r=0.553, P=0.000). Pancreatic ghrelin contents, pancreatic ghrelin mRNA expression, the percentage of insulin (+) cells and ghrelin (+) cells in both groups decreased in an age-dependent manner (F = -49.29 to approximately 427.28, P<0.001). There were differences in the above indexes between N and I group (F = -69.98 to approximately 169.22, P<0.05). Insulin secretion was negatively correlated with ghrelin contents in both groups (r=-0.895, P=0.000; r=-0.458, P=0.002). Percentage of insulin(+) cells was negatively correlated with the percentage of ghrelin (+) cells in pancreatic islets in both groups (r=-0.810,P=0.000; r=-0.714, P=0.000). The distributions of ghrelin (+) cells in pancreatic islets of I group were different from those of N group.

CONCLUSIONThe effects of IUGR on weight, plasma ghrelin levels and insulin secretion of pups rats persist after birth and ghrelin may be involved in the process of insulin resistance in IUGR rats.

Animals ; Animals, Newborn ; Female ; Fetal Growth Retardation ; genetics ; metabolism ; Ghrelin ; blood ; metabolism ; Insulin ; blood ; metabolism ; Insulin Resistance ; physiology ; Insulin-Secreting Cells ; metabolism ; Pregnancy ; RNA, Messenger ; metabolism ; Rats ; Rats, Sprague-Dawley