短链脂肪酸在2型糖尿病发病机制中的作用

短链脂肪酸(SCFA)是由肠道菌群发酵膳食纤维产生的代谢产物,饮食结构变化通过改变肠道菌群结构与功能,影响SCFA的产生.近来研究发现,SCFA通过调节胃肠道激素分泌、胰岛素敏感性及糖、脂代谢,参与了2型糖尿病的发生、发展.对SCFA的深入研究,为阐明2型糖尿病发病机制及其预防和治疗提供了新的思路和靶点.     

Dietary supplementation with n-3 fatty acids may impair glucose homeostasis in patients with non-insulin-dependent diabetes mellitus

The effects on lipoprotein and glucose metabolism of addition of n-3 fatty acids were studied in 14 non-insulin-dependent diabetic patients who were given 10 g of MaxEPA (3 g n-3 fatty acids) or placebo (olive oil) per day in a randomized double-blind cross-over study during two consecutive 8-week periods. After MaxEPA treatment, there was a marked increase in long-chain polyunsaturated fatty acids of the n-3 series in the plasma lipid esters and in the platelet phospholipids, while the n-6 fatty acid content decreased. The very low density lipoprotein (VLDL) triglyceride concentrations decreased significantly (by 22%) on MaxEPA treatment. However, these changes were not significantly different from those observed during the placebo period. The blood glucose concentration tended to increase during MaxEPA treatment, and to decrease during the placebo period, the changes under the two regimes being significantly different (P less than 0.01). In addition, the rate constant for glucose disappearance (k value) for the intravenous insulin-tolerance test, which reflected the peripheral insulin sensitivity, tended to decrease during MaxEPA treatment and increase during administration of the placebo, there being a significant difference (P less than 0.03) between the changes during the two treatments. The reason for the observed changes in blood glucose concentration and peripheral insulin sensitivity is still unclear.     

Non-esterified fatty acids do not contribute to insulin resistance in persons at increased risk of developing Type 2 (non-insulin-dependent) diabetes mellitus

Summary The mechanisms underlying insulin resistance in Type 2 (non-insulin-dependent) diabetes mellitus are not fully understood. An enhanced lipid/non-esterified fatty acid oxidation could provide an explanation. To test this hypothesis we examined the relationship between glucose and lipid metabolism in 44 first-degree relatives (28 glucose-tolerant and 16 glucose-intolerant) of Type 2 diabetic patients and in 18 healthy control subjects. Total body glucose disposal was impaired among both glucose-tolerant and glucose-intolerant relatives compared with control subjects (36.3±3.8 and 30.4±2.7 vs 47.7±3.4 mol · kgLBM^/s-1· min^–1; p < 0.05). The impairment in glucose disposal among the relatives was primarily accounted for by impaired non-oxidative glucose metabolism (14.8±3.0 and 12.5±1.8 vs 25.3±3.1 mol · kgLBM^–1 · min^–1; p <0.05). Plasma non-esterified fatty acid concentrations were similar in both glucose-tolerant and glucose-intolerant relatives and control subjects (646±36,649±43 and 615±41 mol/l) and showed the same degree of suppression by insulin (99±8, 86±7 and 84±9 mol/l). Basal lipid oxidation was similar in all groups (1.29±0.09, 1.52±0.13 and 1.49±0.21 mol · kgLBM^–1· min^–1). Furthermore, insulin suppressed lipid oxidation to the same degree in glucose-tolerant, glucose-intolerant relatives and control subjects (0.65±0.13, 0.88±0.15 and 0.59±0.09mol · kgLBM^–1 · min^–1). An inverse correlation between plasma non-esterified fatty acid concentration and total body glucose disposal was observed in the group of control subjects (r=–0.540; p<0.05), but not among the relatives (r=0.002; p=N.S.). In conclusion the present data challenge the view that the glucose-fatty acid cycle contributes to the insulin resistance seen in first-degree relatives of patients with Type 2 diabetes.     

The concentrations of short-chain fatty acids and other microflora-associated characteristics in faeces from children with newly diagnosed Type 1 diabetes and control children and their family members.

AIMS: The gut flora is quantitatively the most important source of microbial stimulation and may provide a primary signal in the maturation of the immune system. We compared the microflora-associated characteristics (MACs) in 22 children with newly diagnosed diabetes, 27 healthy controls, and their family members to see if there were differences between the children and if there was a familial pattern. METHODS: The MACs were assessed by determining the concentrations of eight short-chain fatty acids (SCFA), mucin, urobilin, b-aspartylglycine, coprastanol and faecal tryptic activity (FTA). RESULTS: There were no statistically significant differences between the concentrations of SCFA in the diabetes and control children. Members of families with a diabetic child had a higher concentration of acetic acid (P < 0.02) and lower concentrations of several other SCFAs than control families (P < 0.05-0.02). The other MACs showed no differences between the children or between the two family groups. CONCLUSION: In this pilot study we saw no differences in the MACs between children with diabetes and their controls. There were, however, some differences between the family members of diabetic children and controls that may indicate a familial pattern regarding the production of SCFAs by the gut flora. The role of the gut flora in relation to the risk of developing Type 1 diabetes needs to be analysed in larger and/or prospective studies.     

Blood rheology and cardiovascular risk factors in type 1 diabetes: relationship with microalbuminuria.

Whole blood and plasma viscosity, erythrocyte aggregation and deformability, plasma fibrinogen, lipids, lipoproteins, apolipoproteins, and measures of blood glucose control were compared between 21 Type 1 diabetic patients with microalbuminuria (overnight albumin excretion rate 30-200 micrograms min-1) and 21 patients with albumin excretion below this range matched for age, sex, and duration of diabetes. Patients with microalbuminuria had significantly higher glycosylated haemoglobin (9.4 +/- 1.6 (+/- SD) vs 7.9 +/- 1.8% (normal range 5.0 to 7.6%)), total-cholesterol (5.6 +/- 1.1 vs 4.6 +/- 1.3 mmol l-1), apolipoprotein B (0.82 +/- 0.21 vs 0.66 +/- 0.14 g l-1), and apolipoprotein B:A1 ratio (0.58 +/- 0.18 vs 0.50 +/- 0.15) than those without microalbuminuria (all p less than 0.05). HDL-cholesterol was also raised (1.71 +/- 0.46 vs 1.43 +/- 0.37 mmol l-1, p less than 0.05). Lipoprotein(a) concentration was possibly higher in the microalbuminuric group (median (95% Cl) 105 (82-140) vs 72 (52-114) mg l-1, p = 0.06). No differences were seen in any of the rheological measurements. These results confirm the presence of potentially atherogenic lipoprotein changes in Type 1 diabetic patients with microalbuminuria, but suggest that altered blood rheology does not predate the development of nephropathy.     

Insulin degludec in Japanese patients with type 1 diabetes mellitus: A randomized controlled trial

Introduction

Insulin degludec is an ultra‐long‐acting insulin with a flat time‐action profile and duration of action >42 h. Data from several studies have shown insulin degludec to have a favorable therapeutic profile in type 1 and type 2 diabetes.

Materials and Methods

This was a 6‐week, parallel‐group, randomized controlled trial carried out in 65 Japanese patients with type 1 diabetes, previously treated with mealtime insulin aspart and either insulin glargine or neutral protamine Hagedorn insulin. Patients were randomized to receive either insulin degludec or insulin detemir, each once daily and at the same unit dose as pretrial basal insulin. During the trial, basal insulin was titrated according to a prespecified algorithm in order to achieve a fasting plasma glucose target of 80–109 mg/dL.

Results

No severe hypoglycemia occurred; there was no significant difference in confirmed hypoglycemia rates with insulin degludec and insulin detemir (rate ratio degludec/detemir 0.78; 95% confidence interval 0.45–1.34). The rate of nocturnal confirmed hypoglycemia was 69% lower with insulin degludec than with insulin detemir (rate ratio 0.31; 95% confidence interval 0.13–0.78). Final fasting plasma glucose levels were similar (insulin degludec 147 mg/dL, insulin detemir 136 mg/dL), despite differing baseline fasting plasma glucose levels.

Conclusions

In conclusion, no concerns relating to hypoglycemia or general safety were observed when initiating insulin degludec in Japanese patients with type 1 diabetes at the same unit dose as previous basal insulin. This trial was registered with ClinicalTrials.gov (no. NCT00841087).     

Basal insulin requirement of youth with type 1 diabetes differs according to age

We investigated the percentage of total basal insulin dose to total daily insulin dose (%TBD) among Japanese youth of different ages with type 1 diabetes. The study enrolled 69 patients with type 1 diabetes who were treated with multiple daily injections of insulin. The participants were divided into the following age groups: group A, 0 to <10 years (n = 18); group B, 10 to <20 years (n = 31) and group C, 20 to <25 years (n = 20). We found no difference in the sex ratio, body mass index, and glycated hemoglobin and 2‐h postprandial C‐peptide levels among the three groups. Participants assigned to group B had a significantly higher percentage of total daily insulin dose than those in group A and group C (49.7 ± 10.4% vs 38.5 ± 13.7% and 38.3 ± 8.2%, P = 0.0005). In conclusion, the basal insulin requirements of Japanese youth with type 1 diabetes might have an age effect that is associated with puberty.     

Lowering fatty acids potentiates acute insulin response in first degree relatives of people with Type II diabetes

Summary Studies have shown that a high plasma non-esterified fatty acid concentration may inhibit glucose induced insulin secretion in vitro and in vivo. The effect of lowering the fatty acid concentration on the acute insulin response was investigated in first degree relatives of people with Type II diabetes in a double-blind, randomised, placebo-controlled trial. Fifty first degree relatives of people with Type II diabetes volunteered for the study. Twenty five were given acipimox (250 mg/day, four times daily) and 25 placebo. The group treated with acipimox had a lower 2-h plasma glucose concentration (6.1 ± 0.2 vs 7.7 ± 0.3 vs mmol/l, p < 0.01); better insulin-mediated glucose uptake (35.4 ± 0.5 vs 28.3 ± 0.4 μmol/kg fat free mass per min, p < 0.01), acute insulin response (68 ± 4.4 vs 46 ± 7.3 mU/l, p < 0.01) and respiratory quotient (0.81 ± 0.02 vs 0.77 ± 0.03, p < 0.05); and a rise in the plasma glucagon (164 ± 63 vs 134 ± 72 ng/l, p < 0.05), growth hormone (1.31 ± 0.13 vs 0.97 ± 0.21 μg/l, p < 0.03) and cortisol (325 ± 41 vs 284 ± 139 nmol/l, p < 0.05) concentrations. The difference in the acute insulin response persisted, even after adjustment for the 2-h plasma glucose concentration, insulin-mediated glucose uptake, the fasting plasma glucagon concentration and the growth hormone concentration (p < 0.05). In a subgroup of eight patients acipimox was compared with acipimox plus intralipid. The acute insulin response (44 ± 5.1 vs 71 ± 5.3 mU/l, p < 0.01) and the insulin-mediated glucose uptake (27.4 ± 0.4 vs 36.7 ± 0.5 μmol/kg fat free mass per min, p < 0.003) were lower with acipimox plus intralipid treatment than with acipimox alone. It is concluded that long term acipimox treatment lowers the plasma fasting free fatty acid concentration and improves the acute insulin response and the insulin mediated glucose uptake. [Diabetologia (1998) 41: 1127–1132] Received: 27 January 1998 and in final revised form 29 April 1998     

Nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus and its association with cardiovascular disease

Introduction

Non-alcoholic fatty liver disease (NAFLD) encompasses a wide spectrum of liver disease that ranges from hepatic steatosis to non-alcoholic steatohepatitis. Obesity and diabetes mellitus are the prime risk factors for NAFLD. The aim of this study was to find out the prevalence of NAFLD among patients with type 2 diabetes mellitus and to detect the association of NAFLD with cardiovascular disease in them.

Insulin resistance in type 1 diabetes

Insulin resistance plays a larger role in the type 1 diabetes disease process than is commonly recognized. The onset of type 1 diabetes is often heralded by an antecedent illness and/or the onset of puberty, both conditions associated with insulin resistance. In the face of a damaged beta-cell and thus reduced insulin secretion, this change is enough to manifest hyperglycemia. During the first year of clinical disease, considerable evidence suggests that the occurrence of clinical remission or 'honeymoon period' is due to a temporary resolution of the insulin-resistant state present at diagnosis. Intensive diabetes management is associated with both improved insulin sensitivity and beta-cell function. This indicates that the historical data on the changes in insulin secretion post-diagnosis may be inappropriate when designing current studies. The known physiological relationship between beta-cell function and insulin sensitivity complicates interpretation of insulin secretion data obtained as part of prevention or intervention trials. While it is recommended that at least a subset of subjects participating in these trials undergo formal measurements of insulin sensitivity to evaluate effects of therapy on this parameter independent of effects on the beta-cell, the sample size must be sufficient to determine an effect if present. Finally, one could speculate that it is possible that subsets of people with mild manifestations of the type 1 autoimmune disease process could benefit from treatments aimed at improving the insulin-resistant state.     

Trends in cardiovascular risk factor management in type 1 diabetes by sex

Aims

DCCT showed that intensive type 1 diabetes management reduces complication incidence but did not focus on other cardiovascular disease risk factors, whose control in type 1 diabetes has not been well-studied. We assessed trends in cardiovascular risk factors in type 1 diabetes and attainment of concurrent American Diabetes Association (ADA) guidelines/recommendations (for HbA1c, blood pressure, LDL cholesterol, triglycerides) for complication prevention.

Evaluating causal associations between chronotype and fatty acids and between fatty acids and type 2 diabetes: A Mendelian randomization study

Background and aimsPreference for activity in the morning or evening (chronotype) may impact type 2 diabetes (T2D) risk factors. Our objective was to use Mendelian randomization (MR) to evaluate whether there are causal links between chronotype and one potential T2D risk factor, total fatty acids (TOTFA), and between TOTFA and T2D.Methods and resultsWe estimated the causal effect of: 1) morning chronotype on TOTFA; and 2) higher TOTFA on T2D. We found that: a) morning compared to evening chronotype was associated with lower TOTFA levels (inverse-weighted variance (IVW) estimate −0.21; 95% CI −0.38, −0.03; raw P = 0.02; FDR-corrected P 0.04) and b) elevated TOTFA levels were protective against T2D (IVW estimate −0.23; 95% CI −0.41, −0.05; raw P = 0.01; FDR-corrected P = 0.03). Based on this finding, we further hypothesized that healthy fats would show a similar pattern and performed MR of a) morning chronotype on omega-3 (Omega-3), monounsaturated (MUFA), and polyunsaturated (PUFA) fatty acids; and b) MR of each of these fat types on T2D. We observed the same mediating-type pattern for chronotype, MUFA, and T2D as we had for chronotype, TOTFA, and T2D, and morning chronotype was associated with lower Omega-3.ConclusionOur findings provide suggestive, new information about relationships among chronotype, TOTFA, and T2D and about chronotype as a factor influencing Omega-3, MUFA, and TOTFA levels. In addition, we validated previous knowledge about MUFA and T2D. Morning chronotypes may predispose towards lower levels of TOTFA and some healthy fats, whereas higher levels of TOTFA and MUFA may protect against T2D.     

Microalbuminuria and cardiovascular risk factors in type 2 diabetes mellitus

Prospective studies have shown that increased urinary albumin excretion is a risk factor for cardiovascular morbidity and mortality in patients with Type 2 diabetes mellitus, but the nature of the association remains unknown. Eighty-five patients aged less than 65 years and not treated with insulin were studied. The overnight albumin excretion rate (AER) was measured in each patient and analysed in relation to several putative risk factors for cardiovascular disease. AER was used both as a continuous variable and after dividing patients into high-risk (AER greater than or equal to 10 micrograms min-1) and low-risk (AER less than 10 micrograms min-1) groups. By both methods of analysis AER was significantly correlated with both seated and supine diastolic blood pressure levels and with resting heart rate. Body mass index and waist-hip ratio appeared higher and HDL-cholesterol lower in the at-risk group, but differences were not statistically significant. The level of Factor VII was not significantly lower in the at-risk group. Little of the cardiovascular risk associated with raised AER can be attributed to associations with conventional risk factors.     

Recent advances in treatment of youth with Type 1 diabetes: better care through technology.

While treatment of Type 1 diabetes mellitus (T1DM) in children and adolescents is especially difficult, recent technological advances have provided new therapeutic options to clinicians and patients. The urgency to achieve strict diabetes control and the introduction of new and improved insulin pumps have been accompanied by a marked increase in use of continuous subcutaneous insulin infusion (CSII) therapy in youth with diabetes. Results of clinical outcome studies indicate that CSII provides a safe and effective alternative to multiple daily injection (MDI) therapy, even when employed in a regular clinic setting in a large number of children. The safety and efficacy of CSII is further enhanced by the introduction of lispro and aspart insulin. The sharper peaks and shorter duration of action of these very rapid-acting insulin analogues provides a means to achieve better control of post-prandial hyperglycaemia with less late post-prandial and nocturnal hypoglycaemia. Glargine insulin, a soluble and essentially peakless long-acting insulin analogue, may provide a better basal insulin for MDI regimens, but there are limited published data with this agent in children with T1DM. A number of systems for pulmonary delivery of insulin are in development and preliminary results of Phase III studies have been promising. Like CSII, inhaled insulin allows the child to take bolus insulin doses before each meal without having to take a premeal injection. A major obstacle to effective treatment is that self-monitoring of three to four blood glucose levels a day often misses the marked glycaemic excursions that characterize T1DM in young patients. On the other hand, new continuous glucose sensing systems provide a wealth of data that can be used to optimize basal and bolus therapy, regardless of how insulin is administered. Even more important, we may finally be at the threshold of development of a practically applicable artificial pancreas.     

2型糖尿病尿微量白蛋白与心血管病危险因素的研究

目的探讨2型糖尿病（T2DM）患者尿微量白蛋白与心血管病危险因素（血糖、血脂、血压、尿酸等）的关系。方法选择192例确诊为T2DM住院患者,分为微量白蛋白尿（MAU）组（n=60）和正常微量白蛋白尿（NAU）组（n=132）,检测患者体质指数（BMI）、血脂、血压、尿酸等相关危险因素,并进行对比分析;同时以尿微量白蛋白为因变量,各相关危险因素为自变量进行了多元线性回归分析,以明确影响2型糖尿病患者尿微量白蛋白增加的因素。结果 MAU组糖化血红蛋白水平（HbA1c）、入院时收缩压（SBP）、舒张压（DBP）水平、血肌酐（Cr）、尿酸（UA）、总胆固醇（TC）、低密度脂蛋白胆固醇（LDL-C）水平及TC、LDL-C、UA、SBP和DBP的异常率明显高于NAU组,而高密度脂蛋白胆固醇（HDL-C）水平明显低于NAU组（P〈0.05～0.01）,多元线性回归分析发现MAU与BMI、SBP、DBP、TC、TG、LDL-C、HbA1c、UA和Cr呈正相关,而与HDL-C呈负相关（P〈0.05～0.01）。结论血脂、血压等多种危险因素的异常影响T2DM患者尿微量白蛋白水平。     

Prevalence of peripheral neuropathy and associated risk factors in children with type 1 diabetes

AimTo detect the prevalence of diabetic polyneuropathy (DPN) in children with type 1 diabetes (T1D) and to identify associated the risk factors.MethodsThis cross-sectional study evaluated children aged between 2 and 16y with T1D for ≥2 y. Detailed neurological examination, neuropathy symptom score, and nerve conduction studies were done in all children to assess nerve dysfunction. Disease-related factors were evaluated for the prediction of neuropathy.ResultsSixty-six children (67% boys) were enrolled. The mean age at the time of diagnosis of T1D was 7.1 ± 2.6 years. The mean duration of diabetes was 4 ± 1.8 years. None of the patients had neuropathy on clinical examination or on the neuropathy symptom score. The prevalence of subclinical DPN was 18.2% (n = 12/66). The type of neuropathy was pure motor (n = 11, 91.6%) and mixed sensorimotor (n = 1, 8.3%). The common peroneal nerve was most commonly affected (n = 6, 50%), followed by the tibial (n = 4, 33.3%) nerve. The most common patterns of nerve involvement were mixed axonal and demyelination (n = 7, 58.3%), followed by axonal (n = 3, 25%) and demyelinating type (n = 2, 16.6%). Children with subclinical DPN had a significant reduction in velocity of tibial, common peroneal, median motor, and ulnar motor nerves; delayed latency in common peroneal, median motor, ulnar motor, and median sensory nerves compared to those without DPN (p value <0.05). A higher body mass index predicted the development of subclinical DPN (p value <0.05).ConclusionNearly one-fifth of children with T1D have subclinical neuropathy as early as two years of the disease. A higher body mass index is significantly associated with DPN. Electrophysiological studies should be performed regularly to screen for nerve dysfunction and its progression.