Genetic susceptibility to non-insulin dependent diabetes mellitus and glucose intolerance are located in HLA region.

OBJECTIVES--To test the hypothesis that the genetic susceptibility to non-insulin dependent diabetes mellitus is the same as that to insulin dependent disease and to see whether glucose intolerance is associated with specific HLA haplotypes. DESIGN--Population based study of men in 1989 first tested for glucose tolerance in 1984. HLA haplotypes, including HLA-A, C, B, DR, and DQ, were defined serologically. HLA haplotype data from a population based Finnish study of childhood diabetes were used for predicting non-insulin dependent diabetes and impaired glucose tolerance. SETTING--Two communities in Finland. SUBJECTS--Representative cohort of Finnish men aged 70-89, comprising 98 men with non-insulin dependent diabetes mellitus and a randomly selected group of 74 men, who served as controls, who were tested for glucose tolerance twice within five years. MAIN OUTCOME MEASURES--Non-insulin dependent diabetes, impaired glucose tolerance, blood glucose concentration. RESULTS--Diabetes associated HLA haplotypes were present in 94% (85/90) of diabetic subjects, 79% (27/34) of subjects with impaired glucose tolerance, and only 13% (3/23) of non-diabetic subjects. In this group of elderly men sensitivity of the diabetes associated HLA haplotypes for non-insulin dependent diabetes and impaired glucose tolerance was 90%, specificity 87%, and predictive power 97%. Mean fasting blood glucose concentration was only just significantly higher in men with diabetes associated haplotypes than in men with no such haplotypes, but there was a substantial difference in blood glucose values two hours after glucose loading (10.4 and 6.4 mmol/l in men with diabetes associated HLA haplotypes and men with no such haplotypes, respectively (p < 0.0001)). CONCLUSIONS--These findings support the hypothesis that specific HLA haplotypes exhibit a common genetic determinant for insulin dependent and non-insulin dependent diabetes. Furthermore, HLA is a major genetic determinant of glucose intolerance in elderly Finnish men. The belief that the HLA predisposition to diabetes is specific for insulin dependent diabetes mellitus is largely incorrect.     

Increased serum levels of interleukin-18 in patients with diabetic nephropathy

In the present study we measured interleukin-18 (IL-18) and tumour necrosis factor-alpha (TNF-alpha) levels by enzyme linked immunosorbent assay (ELISA) in sera from 65 diabetic [30 with type 1 insulin dependent diabetes mellitus (IDDM) and 35 with type 2 non-insulin dependent diabetes mellitus (NIDDM)] patients and 15 healthy volunteers, to investigate their associations with metabolic parameters and to elucidate their roles in the pathogenesis of diabetic complications especially diabetic nephropathy. Levels of IL-18 and TNF-alpha were significantly higher in both IDDM and NIDDM individuals as compared to the control group. Similarly, their levels in patients with diabetic nephropathy increased gradually according to the clinical stage of the disease, being highest in macroalbuminuric stage. Correlation analyses showed that the serum IL-18 and TNF-alpha concentration were positively correlated with each other and positively with fasting plasma glucose (FPG), 2h postprandial glucose, glycosylated hemoglobin (HbA1c), triglyceride, and urinary albumin levels and negative correlation between TNF-alpha and high density lipoprotein cholesterol (HDL-C) were also found in diabetic subjects. High serum levels of IL-18 and TNF-alpha suggested that they might play a role in the pathogenesis of DM and in the development of nephropathy in diabetic patients whether of type 1 or 2.     

Metabolic abnormalities in children of non-insulin dependent diabetics.

Non-insulin dependent diabetes appears to be an inherited condition. A study of young offspring of non-insulin dependent diabetics was conducted to determine whether metabolic abnormalities could be found at a young age before clinical diabetes developed. Thirteen patients with non-insulin dependent diabetes were selected who fulfilled the following criteria: they had a sibling who also had non-insulin dependent diabetes, their spouse was non-diabetic, and the offspring were aged between 12 and 45 years, not diabetic, and available for study. All 32 offspring had a 75 g oral glucose tolerance test, and results in 13 of them, one randomly selected from each family, were compared with 13 controls of similar age, sex, and weight. The offspring had significantly higher fasting concentrations of glucose, higher proportions of haemoglobin A1, and higher concentrations of insulin, C peptide, and glucagon. After glucose challenge the increases in both glucose and C peptide concentrations were significantly greater in the offspring. These differences were maintained in all 32 offspring when compared with 18 controls of similar age, sex, and weight; seven of the 32 offspring had impaired glucose tolerance. These results indicate that young offspring of selected non-insulin dependent diabetics can show extensive metabolic changes including impaired glucose tolerance. These changes are associated with hyperinsulinaemia and hyperglucagonaemia.     

Developing a new model for non-insulin dependent diabetes mellitus (NIDDM) by using the Philippine wild mouse, Mus musculus castaneus.

The Philippine wild-caught castaneus mouse (Mus musculus castaneus) and laboratory mouse (C57BL/6J: B6) were used to develop a new non-insulin dependent diabetes mellitus (NIDDM) model. Offspring from the cross between a wild male and B6 female were backcrossed to the sire. One male which exhibited highest fasting hyperglycemia (190 mg/dl) among eighty-seven backcross offspring was selected at 10 weeks of age, and crossed with a B6 female to comprise the fundamental stock (F0). Thereafter, full-sib mating was performed to develop a new inbred strain named CBD (Castaneus-B6 diabetic) mouse. Mice with relatively higher fasting hyperglycemia among F0 and F1 generations were selected for breeding. From the F2 generation, mice were defined as diabetic when blood glucose levels exceeded 200 mg/dl at 120 min in intraperitoneal glucose tolerance test (IPGTT) at 10 weeks of age, and have been selectively bred. The incidence of diabetic males from the F3-F6 generation fluctuated 45-75% at 10 weeks of age and 59-72% at 20 weeks of age. Diabetic males had about two-fold higher fasting glucose and insulin levels than B6 males. Glucose-stimulated insulin secretion was impaired in diabetic CBD mice compared to B6 males at 20 weeks. Moreover, diabetic mice had slight obesity compared to B6 mice. These facts indicated that diabetic features of CBD mice resemble NIDDM in humans. The CBD strain, characterized by high incidence and early onset of diabetes with mild obesity would be of value as a new NIDDM model. The method, utilizing wild castaneus mouse of different origin from laboratory mice, maybe useful in the development of other animal models.     

Hyperglycemia-induced insulin resistance in diabetic dyslipidemic Yucatan swine

Hyperglycemia, dyslipidemia, and associated insulin resistance are hallmarks of diabetes mellitus. Purposes of the study reported here were to develop practical methods for assessment of in vivo insulin sensitivity and determine contributions of hyperglycemia and dyslipidemia to insulin resistance in the porcine model of alloxan-induced diabetes mellitus and dyslipidemia. Male Yucatan swine groups were treated for 20 weeks: control (C), high fat-fed (2% cholesterol) hyperlipidemic (H), alloxan-induced diabetic normolipidemic (D), diabetic high fat-fed (diabetic dyslipidemic, DD), and diabetic dyslipidemic treated with the lipid-lowering agent atorvastatin (DDA). Plasma cholesterol concentration increased sixfold in animals of groups H, DD, and DDA, whereas triglyceride concentration increased threefold in animals of group DD only. Diabetics had decreases in glucose tolerance and pancreatic immunostaining for insulin. Use of the gold standard hyperinsulinemic euglycemic clamp procedure indicated that maximal insulin-stimulated glucose uptake was similar to that in humans, but this method was not practical for use in pigs. Instead, a more convenient and valid insulin sensitivity test involving suppression of insulin secretion with somatostatin and a single insulin injection was used. Insulin sensitivity was greatly impaired by anesthesia with isoflurane, but was not affected by use of the anxiolytic agent diazepam. Insulin sensitivity decreased by 75% in diabetics (groups D, DD, DDA), compared with animals of groups C and H, and was inversely related to fasting blood glucose concentration (r = -0.72). Insulin treatment to restore blood glucose values of diabetics (> 250 mg/dl) to near control values (< 100 mg/dl) promptly restored insulin sensitivity to control values. We conclude that hyperglycemia is a major cause of insulin resistance in the porcine model of alloxan-induced diabetes mellitus and dyslipidemia.     

Delta aminolevulinate dehydratase (ALA-D) activity in human and experimental diabetes mellitus

The haem pathway is impaired in porphyrias and a frequent coexistence of diabetes mellitus and porphyria disease has been reported. We have therefore decided to investigate delta-aminolevulinate dehydratase, one of the more sensitive enzymes in the haem pathway, in both human diabetic patients and diabetic rats. We have studied 131 diabetes mellitus patients, 32 insulin dependent and 99 non-insulin dependent. The latter group was further subdivided according to treatment: diet alone (n = 24), diet plus oral hypoglycemic agents (n = 28) and diet plus insulin (n = 47). We have also performed similar studies in the rat model of diabetes mellitus, induced in 11 Wistar rats by streptozotocin. Control groups of both humans and animals were used. Erythrocytic aminolevulinate dehydratase activity was reduced in both insulin dependent and non-insulin dependent diabetic patients as compared to their controls (p < 0.001). This activity was only partially restored by addition of zinc and thiols to the incubation media. In insulin-dependent diabetes mellitus, reduction of enzyme activity was related to the glycosilated hemoglobin concentration (p < 0.05) and in non-insulin dependent diabetes mellitus to the glycemia (p < 0.01). In the diabetic rat, aminolevulinate dehydratase activity was diminished on both erythrocytes (p < 0.01) and hepatic tissue (p < 0.01) when compared to the control group. The decrease in activity of erythrocyte aminolevulinate dehydratase observed in diabetic patients, may represent an additional and useful parameter for the assessment of the severity of carbohydrate metabolism impairment.     

Effect of enprostil on plasma glucose, insulin and lipid metabolism in patients with non-insulin-dependent diabetes mellitus

Measurements of various aspects of glucose, insulin and lipid metabolism were made before and after the administration of enprostil (a synthetic dehydroprostaglandin E2) for one week to ten patients with non-insulin-dependent diabetes mellitus (NIDDM). Both fasting (P less than 0.01) and postprandial (P less than 0.001) plasma glucose concentrations were significantly lower after one week of enprostil, and 24 hour urinary glucose excretion was reduced from (mean +/- SEM) 47 +/- 14 to 25 +/- 9 g/day. There was no change in either fasting or postprandial insulin concentration, but the postprandial GIP response was also significantly reduced (P less than 0.001). In addition, there were significant reductions in postprandial plasma free fatty acid (P less than 0.05) and triglyceride (P less than 0.001) concentrations, associated with a modest fall in fasting plasma triglyceride (P less than 0.05) and cholesterol (P less than 0.07) concentrations when measured after one week of treatment with enprostil. These results raise the possibility that enprostil may be of some benefit in the treatment of patients with non-insulin-dependent diabetes.     

Risk factors for developing non-insulin dependent diabetes: a 10 year follow up of men in Uppsala.

OBJECTIVE--To analyse anthropometric and metabolic characteristics as risk factors for development of non-insulin dependent diabetes mellitus in middle aged normoglycaemic men. DESIGN--Prospective population study based on data collected in a health survey and follow up 10 years later. SETTING--Uppsala, a middle sized city in Sweden. SUBJECTS--2322 men aged 47-53, of whom 1860 attended the follow up 7-14 years later, at which time they were aged 56-64. MAIN OUTCOME MEASURES--Incidence of non-insulin dependent diabetes. RESULTS--In a multivariate logistic regression analysis, variations of 1 SD from the mean of the group that remained euglycaemic were used to calculate odds ratios and 95% confidence intervals. Blood glucose concentration 60 minutes after the start of an intravenous glucose tolerance test (odds ratio = 5.93, 95% confidence interval 3.05 to 11.5), fasting serum insulin concentration (2.12, 1.54 to 2.93), acute insulin increment at an intravenous glucose tolerance test (1.71, 1.21 to 2.43), body mass index (1.41, 1.01 to 1.97), and systolic blood pressure (1.23, 0.97 to 1.56) were independent predictors of diabetes. In addition, the use of antihypertensive drugs at follow up (selective or unselective beta blocking agents, thiazides, or hydralazine) was an independent risk factor (1.70, 1.11 to 2.60). CONCLUSIONS--Metabolic and anthropometric characteristics associated with or reflecting insulin resistance as well as a poor acute insulin response to glucose challenge were important predictors of future diabetes in middle aged men. Antihypertensive drugs were found to constitute a further, iatrogenic risk factor.     

The effect of regular alcohol use on the management of non-insulin diabetes mellitus.

This is a retrospective study, in which we investigated the impact of regular alcohol use on the clinical management of non-insulin dependent diabetes mellitus (NIDDM) patients from the outpatient clinic of the VA Medical Center in New Orleans, Louisiana. The study population included randomly selected NIDDM patients of which 40% used alcohol regularly. The fasting blood sugar (FBS) in non-users of alcohol stayed in the "normal" (< or = 140 mg/dl) and "acceptable " (< or = 175 mg/dl) range and that of regular users of alcohol remained at the "fair" (< or = 235 mg/dl) and "poor" (> 235 mg/dl) range. NIDDM patients who were regular users of alcohol had a higher frequency of dose adjustments than that of non-users of alcohol (96% vs 4%, respectively). The treatment failure was significantly higher among patients who regularly used alcohol than among those who abstained (90 vs 10%, respectively). On the basis of our findings, it was recommended that attending physician should routinely identify the regular alcohol users and monitor blood alcohol levels of ambulatory NIDDM patients during their follow-up visits. Also, complete cessation of alcohol consumption should be established prior to making dosage adjustment in situations where the oral hypoglycemic agent fails.     

Extract of Ocimum canum lowers blood glucose and facilitates insulin release by isolated pancreatic β-islet cells

Aqueous extract of Ocimum canum Sim, (Lamiaceae) is used by some Ghanaians to manage diabetes mellitus. In vivo modulation of levels of fasting blood glucose by 0. canum extract was evaluated in type-II diabetes mellitus using the C57BL/KsJ db/db genetically diabetic animal model, and its effects on glucose-stimulated insulin release in vitro were monitored using isolated rat pancreatic beta-islet cells. The results showed that fasting blood glucose levels and body weight decreased significantly (p < 0.05) in diabetic and non-diabetic C57BL/KsJ mice, which were administered aqueous extract of 0. canum. In vitro, the 0. canum extract significantly enhanced insulin release from isolated rat pancreatic beta-islet cells. Insulin release was found to be dependent on glucose concentration and increased with increasing O. canum concentration in the incubation medium up to an optimum extract concentration of 0.03 mg/ml. Release of the hormone decreased beyond this concentration of extract in the medium. Addition to the medium of Desmodium adscendens, a plant preparation used to manage inflammatory disorders, did not increase but rather inhibited insulin secretion by the pancreatic beta-islet cells. These results could explain the use of 0. canum in Ghanaian folk medicine to manage diabetes mellitus.     

Comparison of tests for glycated haemoglobin and fasting and two hour plasma glucose concentrations as diagnostic methods for diabetes.

OBJECTIVE--To compare the ability of tests measuring two hour plasma glucose, fasting plasma glucose, and glycated haemoglobin concentrations in predicting the specific microvascular complications of non-insulin dependent diabetes mellitus. DESIGN--Cross sectional and longitudinal analysis of the relation between complications and concomitant results of the three tests. SETTING--Gila River Indian Community, Arizona. SUBJECTS--Pima Indians (cross sectional, n = 960), aged 25 years or above who were not receiving insulin or oral hypoglycaemic treatment at the baseline examination. MAIN OUTCOME MEASURES--Development of retinopathy and nephropathy. RESULTS--Cross sectionally, frequency distributions of logarithms of the three sets of results were bimodal, with the prevalence of retinopathy and nephropathy being, respectively, 12.0-26.7 and 3.9-4.2 times as high above as below cut off points which minimised overlap (two hour plasma glucose concentration 12.6 mmol/l; fasting plasma glucose concentration 9.3 mmol/l; glycated haemoglobin (HbA1c) concentration 7.8%). Longitudinally, each of the three measures of glycaemia significantly predicted the development of retinopathy (P < 0.0001) and nephropathy (P < 0.05). Receiver operating characteristic curves showed that two hour plasma glucose concentration was superior to fasting plasma glucose concentration (P < 0.05) for prevalent cases of retinopathy, but otherwise no variable had a significant advantage for detecting incident or prevalent cases of either complication. CONCLUSIONS--These findings suggest that determination of glycated haemoglobin or fasting plasma glucose concentrations alone may be acceptable alternatives to measuring glucose concentration two hours after challenge with 75 g glucose for the diagnosis of diabetes.     

Pancreatic B-cell function in non-insulin-dependent diabetes mellitus during successive periods of sulfonylurea and insulin treatment: serum C-peptide response to glucagon and urine C-peptide excretion

Serum C-peptide responses to glucagon and daily urine C-peptide excretion in successive periods of different treatment in two groups of patients with non-insulin-dependent diabetes mellitus (NIDDM) (mean interval between two tests less than 1 month) were compared. In group A patients (n = 8), the glycemic control was improved after transferring the treatment from sulfonylurea (SU) to insulin (fasting plasma glucose: SU: 192 +/- 47, insulin: 127 +/- 21 mg/dl, mean +/- S.D., p less than 0.01). Fasting serum C-peptide immunoreactivity (CPR) was significantly lower at the period of insulin treatment (SU: 1.93 +/- 1.01, insulin: 1.47 +/- 0.79 ng/ml, p less than 0.05), but there was no difference in the increase in serum CPR (maximal--fasting) (delta serum CPR) during glucagon stimulation in the two periods of treatment (SU: 1.70 +/- 0.72, insulin: 1.47 +/- 0.98 ng/ml). In group B patients (n = 7), there was no significant difference in glycemic control after transferring the treatment from insulin to SU (fasting plasma glucose: insulin: 127 +/- 24, SU: 103 +/- 13 mg/dl). Fasting serum CPR was significantly lower during the period of insulin treatment (insulin: 1.39 +/- 0.64, SU: 2.21 +/- 0.86 ng/ml, p less than 0.025), but delta serum CPR during glucagon stimulation still showed no significant difference between the two periods (insulin: 1.97 +/- 1.16, SU: 2.33 +/- 1.57 ng/ml).(ABSTRACT TRUNCATED AT 250 WORDS)     

Factors predicting the course of diabetes mellitus in hyperthyroid patients

The relationship between changes in glucose tolerance with treatment of hyperthyroidism and various factors that might be relevant to carbohydrate metabolism were investigated in 64 hyperthyroid patients with abnormal glucose tolerance, including 35 cases with fasting plasma glucose (FPG) levels of 140 mg/dl or more. All patients had diffuse toxic goiter. After correction of the hyperthyroidism, glucose intolerance improved in almost all cases, even in cases with fasting hyperglycemia, but diabetes mellitus in patients with FPG above 140 mg/dl and/or delta IRI/delta PG X 30' during a 50-g oral glucose tolerance test below 0.10, persisted. Patients who showed diabetic glucose tolerance even after remission from thyroid dysfunction had significantly lower delta IRI/delta PG X 30' values and a higher incidence of family histories of diabetes mellitus than those not showing diabetic glucose tolerance. There were no significant differences in serum T3 and T4 levels between these two groups of patients. The findings suggest that predisposition to diabetes may be an important factor in persistent glucose intolerance in the hyperthyroidism of Graves' disease. The FPG and delta IRI/delta PG X 30' values may be useful in predicting which patients with hyperthyroidism will have permanent diabetes.     

Insulin glargine maintains equivalent glycemic control and better lipometabolic control than NPH insulin in type 1 diabetes patients who missed a meal.

Our goal was to investigate blood glucose and lipometabolism control in type 1 diabetes patients who missed breakfast and the accompanying insulin injection of NPH insulin (NPH) or insulin glargine (glargine) as part of a basal-bolus regimen. This was a multi-center, open-label, controlled study in adults (> or =18 years) with HbA (1c)< or =11.5% on insulin therapy with NPH as basal insulin. Patients were randomized to receive prandial insulin plus either bedtime glargine (n=28) or NPH (n=32). Insulin was titrated to target fasting blood glucose levels 80-130 mg/dl at 06:00-07:00. Patients had no intake of insulin or food between 22:00 and 12:00 the next day. The change in blood glucose levels (07:00-11:00) was similar (27.5 mg/dl vs. 35.4 mg/dl), but the mean blood glucose level was higher with glargine vs. NPH at 22:00 (158.2 mg/dl vs. 130.2 mg/dl). During the period without insulin or food intake, blood glucose decreased with glargine (-25.8 mg/dl) and increased with NPH (+9.1 mg/dl; p=0.0284). Nonesterified fatty acid (07:00 and 09:00-12:00) and beta-hydroxybutyrate (07:00 and 10:00-12:00) levels were lower with glargine vs. NPH (both p<0.05). For patients who miss a morning meal, glargine is associated with maintained glycemic and lipometabolic control compared with NPH insulin.     

Effect of short-term clofibrate on glucose metabolism and insulin secretion in patients with mild maturity-onset diabetes mellitus

The effect of 1 week clofibrate administration on glucose and insulin responses to oral glucose and to intravenous tolbutamide was evaluated in 21 patients with mild maturity-onset diabetes (fasting plasma glucose 108-152 mg/100 ml). After treatment, oral glucose tolerance and hypoglycaemic effect of tolbutamide were significantly improved; plasma insulin response was reduced after glucose and unmodified after tolbutamide; fasting plasma glucose was also significantly reduced. These findings did not correlate with the observed fall in serum lipids. Short-term clofibrate improves glucose metabolism in mild diabetes irrespective of its effects on lipid metabolism. It is suggested that the drug's action may be mediated by reduced insulin resistance.     

二甲双胍联合西格列汀对2型糖尿病患者氧化应激、胰岛素抵抗的影响

目的:探讨二甲双胍联合西格列汀对2型糖尿病患者氧化应激、胰岛素抵抗的影响。方法:收集我院就诊或住院治疗的80例2型糖尿病患者,随机分为实验组和对照组,每组40例。两组患者入院后均给予相应的治疗措施,对照组患者给予二甲双胍250 mg/次,2次/d;实验组患者在对照组的基础上给予西格列汀100 mg/次,1次/d,治疗均连续8周。治疗结束后对患者血清丙二醛(MDA)、8异前列腺素F2α(8-iso-PGF2α)、空腹血糖(FBG)、空腹胰岛素(FINS)、胰岛素抵抗指数(HOMA-IR)以及患者临床治疗效果进行检测并比较。结果:与治疗前相比,治疗后两组患者MDA、8-iso-PGF2α、FBG、FINS以及HOMA-IR水平均下降(P0.05);与对照组相比,实验组患者MDA、8-iso-PGF2α、FBG、FINS以及HOMA-IR水平较低(P0.05),临床治疗总有效率较高(P0.05)。结论:二甲双胍联合西格列汀能够降低2型糖尿病患者血糖水平,降低MDA、8-iso-PGF2α水平,减轻氧化应激反应,降低胰岛素抵抗,临床疗效较好。     

The Impact of Elevated Blood Glycemic Level of Patients with Type 2 Diabetes Mellitus on the Erythrocyte Membrane: FTIR Study

In developed countries, medical awareness about the disease and how to deal with it is less acknowledged. With diabetes mellitus the situation becomes more serious due to the fact that it affects nearly all parts of the body and may lead to loss of vision. In this study, the variation of blood glucose level of type 2 diabetic patients was considered, and its effect(s) on their blood erythrocyte membranes was studied by Fourier transform infrared spectroscopy. Patients with type 2 diabetes mellitus were classified into two groups with mean fasting blood glucose level of 185 mg/dl (D-185 group) and 285 mg/dl (D-285 group). For comparison, healthy individuals were involved where their mean fasting blood glucose level is 86 mg/dl. Type 2 diabetes mellitus was found to induce change in the lipid and protein components and causing some important structural changes in the protein secondary structure with change in the β-sheet and β-turn structures at D-285 mg/dl group. Erythrocyte membrane disorder was increased associated with restriction in the vibrational motion around the phospholipids interface region.     

Biotin supplementation improves glucose and insulin tolerances in genetically diabetic KK mice

Because biotin treatment may lower blood glucose in insulin-dependent diabetes, we chose to study such an effect in non-insulin dependent diabetes. Twenty-six diabetic KK mice, moderately hyperglycemic and insulin resistant, were treated for 10 weeks: 9 animals with 2 mg of biotin/Kg, 8 with 4 mg of biotin/Kg, and 9 with saline (controls). Blood glucose levels, oral glucose tolerance, insulin response to oral glucose, and blood glucose decrease in response to insulin were quantitated. Compared to controls, biotin treatment lowered post-prandial glucose levels, and improved tolerance to glucose and insulin resistance. Serum immunoreactive insulin levels in biotin-treated mice were like the controls.     

Comparison of high fibre diets,basal insulin supplements,and flexible insulin treatment for non-insulin dependent (type II) diabetics poorly controlled with sulphonylureas.

OBJECTIVE--To compare high fibre diet, basal insulin supplements and a regimen of insulin four times daily in non-insulin dependent (type II) diabetic patients who were poorly controlled with sulphonylureas. DESIGN--Run in period lasting 2-3 months during which self monitoring of glucose concentration was taught, followed by six months on a high fibre diet, followed by six months'' treatment with insulin in those patients who did not respond to the high fibre diet. SETTING--Teaching hospital diabetic clinics. PATIENTS--33 patients who had had diabetes for at least two years and had haemoglobin A1 concentrations over 10% despite receiving nearly maximum doses of oral hypoglycaemic agents. No absolute indications for treatment with insulin. INTERVENTIONS--During the high fibre diet daily fibre intake was increased by a mean of 16 g (95% confidence interval 12 to 20 g.) Twenty five patients were then started on once daily insulin. After three months 14 patients were started on four injections of insulin daily. ENDPOINT--Control of diabetes (haemoglobin A1 concentration less than or equal to 10% and fasting plasma glucose concentration less than or equal to 6 mmol/l) or completion of six months on insulin treatment. MEASUREMENTS AND MAIN RESULTS-- No change in weight, diet, or concentrations of fasting glucose or haemoglobin A1 occurred during run in period. During high fibre diet there were no changes in haemoglobin A1 concentrations, but mean fasting glucose concentrations rose by 1.7 mmol/l (95% confidence interval 0.9 to 2.5, p less than 0.01). With once daily insulin mean concentrations of fasting plasma glucose fell from 12.6 to 7.6 mmol/l (p less than 0.001) and haemoglobin A1 from 14.6% to 11.2% (p less than 0.001). With insulin four times daily concentrations of haemoglobin A1 fell from 11.5% to 9.6% (p less than 0.02). Lipid concentrations were unchanged by high fibre diet. In patients receiving insulin the mean cholesterol concentrations fell from 7.1 to 6.4 mmol/l (p less than 0.0001), high density lipoprotein concentrations rose from 1.1 to 1.29 mmol/l (p less than 0.01), and triglyceride concentrations fell from 2.67 to 1.86 mmol/l (p less than 0.05). Patients taking insulin gained weight and those taking it four times daily gained an average of 4.2 kg. CONCLUSIONS--High fibre diets worsen control of diabetes in patients who are poorly controlled with oral hypoglycaemic agents. Maximum improvements in control of diabetes were achieved by taking insulin four times daily.     

United Kingdom Prospective Diabetes Study (UKPDS). 13: Relative efficacy of randomly allocated diet,sulphonylurea, insulin,or metformin in patients with newly diagnosed non-insulin dependent diabetes followed for three years.

OBJECTIVE--To assess the relative efficacy of treatments for non-insulin dependent diabetes over three years from diagnosis. DESIGN--Multicentre, randomised, controlled trial allocating patients to treatment with diet alone or additional chlorpropamide, glibenclamide, insulin, or metformin (if obese) to achieve fasting plasma glucose concentrations < or = 6 mmol/l. SETTING--Outpatient diabetic clinics in 15 British hospitals. SUBJECTS--2520 subjects who, after a three month dietary run in period, had fasting plasma glucose concentrations of 6.1-14.9 mmol/l but no hyperglycaemic symptoms. MAIN OUTCOME MEASURES--Fasting plasma glucose, glycated haemoglobin, and fasting plasma insulin concentrations; body weight; compliance; and hypoglycaemia. RESULTS--Median fasting plasma glucose concentrations were significantly lower at three years in patients allocated to chlorpropamide, glibenclamide, or insulin rather than diet alone (7.0, 7.6, 7.4, and 9.0 mmol/l respectively; P < 0.001) with lower mean glycated haemoglobin values (6.8%, 6.9%, 7.0%, and 7.6%, respectively; P < 0.001). Mean body weight increased significantly with chlorpropamide, glibenclamide, and insulin but not diet (by 3.5, 4.8, 4.8, and 1.7 kg; P < 0.001). A similar pattern was seen for mean fasting plasma insulin concentration (by 0.9, 1.2, 2.4, and -0.1 mU/l; P < 0.001). In obese subjects metformin was as effective as the other drugs with no change in mean body weight and significant reduction in mean fasting plasma insulin concentration (-2.5 mU/l; P < 0.001). More hypoglycaemic episodes occurred with sulphonylurea or insulin than with diet or metformin. CONCLUSION--The drugs had similar glucose lowering efficacy, although most patients remained hyperglycaemic. Long term follow up is required to determine the risk-benefit ratio of the glycaemic improvement, side effects, changes in body weight, and plasma insulin concentration.