The impact of pioglitazone on glycemic control and atherogenic dyslipidemia in patients with type 2 diabetes mellitus

BACKGROUND: To evaluate the glycemic control, lipid effects, and safety of pioglitazone in patients with type 2 diabetes mellitus. DESIGN AND METHODS: Patients (n = 197) with type 2 diabetes mellitus, a hemoglobin A1c (HbA1c) > or = 8.0%, fasting plasma glucose (FPG) > 7.7 mmol/l (140 mg/dl), and C-peptide > 0.331 nmol/l (1 ng/ml) were enrolled in this 23-week multi-center (27 sites), double-blind clinical trial and randomized to receive either a placebo or pioglitazone HCl 30 mg (pioglitazone), administered once daily, as monotherapy. Patients were required to discontinue all anti-diabetic medications 6 weeks before receiving study treatment. Efficacy parameters included HbA1c fasting plasma glucose (FPG), serum C-peptide, insulin, triglycerides (Tg), and cholesterol (total cholesterol [TC], high-density lipoprotein-cholesterol [HDL-C], low-density lipoprotein-cholesterol [LDL-C]). Adverse event rates, serum chemistry, and physical examinations were recorded. RESULTS: Compared with placebo, pioglitazone significantly (P= 0.0001) reduced HbA1c (-1.37% points), FPG (-3.19 mmol/l; -57.5 mg/dl), fasting C-peptide (-0.076+/-0.022 nmol/l), and fasting insulin (-11.88+/-4.70 pmol/l). Pioglitazone significantly (P < 0.001) decreased insulin resistance (HOMA-IR; -12.4+/-7.46%) and improved beta-cell function (Homeostasis Model Assessment (HOMA-BCF); +47.7+/-11.58%). Compared with placebo, fasting serum Tg concentrations decreased (-16.6%; P = 0.0178) and HDL-C concentrations increased (+12.6%; P= 0.0065) with pioglitazone as monotherapy. Total cholesterol and LDL-C changes were not different from placebo. The overall adverse event profile of pioglitazone was similar to that of placebo, with no evidence of drug-induced elevations of serum alanine transaminase (ALT) concentrations or hepatotoxicity. CONCLUSIONS: Pioglitazone improved insulin resistance and glycemic control, as well as Tg and HDL-C - which suggests that pioglitazone may reduce cardiovascular risk for patients with type 2 diabetes.     

Proinflammatory and atherogenic activity of monocytes in type 2 diabetes

Cytokines secreted by the monocyte–macrophage system play a key role in the progression of atherosclerotic lesions in Type 2 diabetes. The objectives of this study were to assess the influence of cytokine gene expression in monocytes from patients with Type 2 diabetes on direct markers of endothelial injury with regard to clinically manifest atherosclerosis.MethodsMonocytes from 58 patients with Type 2 diabetes and from 22 age-matched healthy volunteers of a control group were isolated in order to assess expression of tumor necrosis factor α (TNFα), interleukin (IL)-6, IL-8 and IL-10 cytokines (RTPCR, Applied Biosystems). Thrombomodulin concentration was determined using a Diagnostica Stago Immunoenzymatic assay, and circulating endothelial cell numbers were assayed using immunofluorescence studies with CLB-HEC19 antibodies.ResultsIn 28 patients, TNFα expression in monocytes was observed. In these patients, as compared to those with undetectable levels of this cytokine's expression, higher hemoglobin A_1c (P=.012) and thrombomodulin (P=.005) concentrations were found. IL-8 expression was determined in 36 patients. Higher expression of TNFα (P=.048) and IL-8 (P=.049) was detected in patients with peripheral arterial disease in contrast to those free from this complication.ConclusionTNFα and IL-8 play a significant role in the proatherogenic activity of monocytes in Type 2 diabetes. The TNFα-connected activity of monocytes may directly determine endothelial dysfunction and injury. The location of atherosclerosis should be taken into account in the assessment of the proinflammatory activity of peripheral blood monocytes.     

Dyslipidemia in type 2 diabetes mellitus

Cardiovascular disease is a significant cause of morbidity and mortality in patients with diabetes mellitus (DM). DM is now recognized as a risk equivalent for coronary heart disease. The lipid profile in patients with type 2 DM is characterized by elevated triglycerides, low levels of high-density lipoprotein cholesterol, and small dense low-density lipoprotein cholesterol (LDLC) particles and is believed to be a key factor promoting atherosclerosis in these patients. Both primary and secondary prevention studies have provided ample evidence that aggressive statin therapy reduces cardiovascular end points in patients with DM. In all persons with DM, current treatment guidelines recommend reduction of LDLC to less than 100 mg/dL, regardless of baseline lipid levels. Lowering LDLC to less than 70 mg/dL may provide even greater benefits, particularly in very high risk patients with DM and coronary heart disease.     

Narrative review: ketosis-prone type 2 diabetes mellitus

Several investigators have reported that more than half of African-American persons with new diagnoses of diabetic ketoacidosis have clinical, metabolic, and immunologic features of type 2 diabetes during follow-up. These patients are usually obese, have a strong family history of diabetes, have a low prevalence of autoimmune markers, and lack a genetic association with HLA. Their initial presentation is acute, with a few days to weeks of polyuria, polydipsia, and weight loss and lack of a precipitating cause of metabolic decompensation. At presentation, they have markedly impaired insulin secretion and insulin action, but intensified diabetic management results in significant improvement in beta-cell function and insulin sensitivity sufficient to allow discontinuation of insulin therapy within a few months of follow-up. On discontinuation of insulin therapy, the period of near-normoglycemic remission may last for a few months to several years. The absence of autoimmune markers and the presence of measurable insulin secretion have proven useful in predicting near-normoglycemic remission and long-term insulin dependence in adult patients with a history of diabetic ketoacidosis. This clinical presentation is commonly reported in African and African-American persons but is also observed in Hispanic persons and those from other minority ethnic groups. The underlying mechanisms for beta-cell dysfunction in ketosis-prone type 2 diabetes are not known; however, preliminary evidence suggests an increased susceptibility to glucose desensitization.     

Weight gain in type 2 diabetes mellitus

OBJECTIVE: To investigate the potential causes of weight gain using insulin and combination therapy in type 2 diabetes. DESIGN AND METHODS: This was an open-label prospective study of 6-month duration. Randomization was performed to insulin monotherapy, insulin and pioglitazone 30 mg daily, or insulin and metformin up to 2000 mg daily. Fifty-seven subjects with poorly controlled type 2 diabetes were enrolled. The goal was to achieve a normal haemoglobin A1c (HbA1c) (<5.6%). Weight, resting energy expenditure (REE), reported energy intake and total energy expenditure, HbA1c, glycosuria, plasma leptin, ghrelin and adiponectin levels, and body fat were measured. RESULTS: A total of 49 subjects completed the study. At baseline, weight was 89.4 +/- 22.9 kg and HbA1c was 11.1 +/- 1.5%. Weight increased by 7.46, 7.60 and 7.12 kg in the monotherapy, metformin and pioglitazone groups, respectively [p = 0.98 between and <0.0001 within the groups by repeated measures-analysis of variance (RM-anova)]. HbA1c dropped to 7.8 +/- 0.9% in the monotherapy arm, 7.6 +/- 1.0% in the metformin arm and 7.2 +/- 1.2% in the pioglitazone arm. Reported energy intake decreased. Glycosuria decreased but was not correlated with weight gain, while HbA1c changes were correlated with weight gain. REE per lean mass decreased (p = 0.04 by RM-anova). The subcutaneous fat areas in the insulin monotherapy and pioglitazone arms showed increases (p = 0.02 and 0.004 respectively). CONCLUSIONS: Weight gain was probably not due to an increase in food intake, while REE per lean body mass decreased, suggesting a role for increased efficiency in fuel usage due to improved glycaemic control. A drop in glycosuria probably also contributed to weight gain. In the monotherapy and pioglitazone arms, the subcutaneous fat areas increased.     

Thiazolidinedione derivatives in type 2 diabetes mellitus

In Europe, the thiazolidinedione derivatives pioglitazone and rosiglitazone have been approved for the treatment of type 2 diabetes mellitus either as monotherapy for patients with intolerance or contraindications to metformin or in combination therapy. This class of drugs seems particularly suited for obese patients, but is currently not considered as a first choice for monotherapy. The efficacy with respect to blood glucose lowering is comparable with sulphonylurea (SU) derivatives and with metformin. Long-term data with respect to efficacy and side effects are still limited.     

Auditory acuity in type 2 diabetes mellitus

BACKGROUND AND OBJECTIVES:

The relationship between diabetes and hearing loss has been debated for many years. Hyperglycemia appears to have an effect on hearing loss and the proposed mechanisms are microangiopathy, neuropathy or a combination of both. The objective of this study was to evaluate a cross section of hyperglycemic subjects with age- and sex-matched normoglycemic controls with pure tone audiometry and compare the differences.

MATERIALS AND METHODS:

Forty-one type 2 diabetes mellitus subjects and 41 age- and sex-matched normoglycemic controls were subjected to a pure tone audiometric assessment followed by evaluation of their glycemic status and degree of glycemic control. The resulting data was statistically analyzed.

RESULTS:

The auditory thresholds in hyperglycemic subjects were higher in all age groups in all the frequencies suggestive of sensorineural hearing loss. The hyperglycemic subjects with poor control of their blood sugar levels (HbA1C > 8%) had elevated auditory thresholds in all the test frequencies. The fasting blood sugar level in hyperglycemic subjects showed a trend towards significant difference at higher frequencies, the postprandial blood sugar levels showed significant differences at higher frequencies. There was no effect of duration of diabetes mellitus on the hearing thresholds in hyperglycemic subjects.

CONCLUSION:

Subjects with hyperglycemia have a sensorineural hearing loss when evaluated with a pure tone audiometer in all frequencies than a normoglycemic control group. The study showed that post prandial blood sugar levels and HbA1C levels had a direct bearing on the auditory acuity of the hyperglycemic subjects.     

Ramadan fasting in type 2 diabetes mellitus

This study was designed to assess the effects of fasting during Ramadan on weight, blood pressure, metabolic control and plasma lipoproteins in diabetic patients. This study was conducted in December 2000 (Ramadan 1421) when the length of fasting was 12 hours a day. It included 38 type 2 diabetic patients (20 males and 18 females). Mean patient age was 51.410.5 years and mean body mass index (BMI) 28.94.7kg/m2. Three patients were treated with diet and 35 with oral hypoglycemic agents. Clinical and biochemical parameters were evaluated during three periods: three weeks before Ramadan (T0), at the fourth week of Ramadan (T1) and three weeks after the end of Ramadan (T2). During the month of Ramadan, a decrease in weight (0.52kg) and no change in blood pressure were observed. No metabolic complication occurred in our patients. A significant effect of Ramadan fasting was observed on glycemic control and lipoprotein levels. In patients whose fructosamine level before Ramadan was higher than 340micromol/l, plasma fasting glucose and serum fructosamine increased during Ramadan (p<0.003) and returned to initial levels at the end of Ramadan T2; in these patients also, a decrease of HDL-cholesterol (p<0.01) associated with an increase of LDL-cholesterol (p<0.003) were observed at T1 and disappeared at T2. But, in patients whose fructosamine level at T0 was lower than 340micromol/l, no effect on glycemic control and no significant effect on serum lipoprotein levels were found during Ramadan month. Ramadan fasting in type 2 diabetic patients seems to cause slight effects on glycemia and lipoprotein levels when previous metabolic control is quite good; but fasting induces more deterioration when previous control is poor.     

Non-alcoholic steatohepatitis in type 2 diabetes mellitus

BACKGROUND AND AIMS: Non-alcoholic steatohepatitis (NASH) is commonly associated with type 2 diabetes mellitus (DM). Prevalence of NASH in type 2 DM has not been well studied and there is an epidemic rise in type 2 DM in Asian and Western populations. Its association with chronic liver disease in the form of NASH makes it an important health problem. Hence we have studied its prevalence and correlation of biochemical parameters with histological grades of non-alcoholic fatty liver disease (NAFLD) in otherwise asymptomatic type 2 DM patients. METHODS: One hundred and forty-eight individuals were screened. Forty-eight individuals were excluded due to history of alcohol intake or liver disease as a result of other causes. One hundred non-alcoholic individuals with type 2 DM underwent abdominal ultrasonography (US abdomen). Forty-nine patients had evidence of fatty liver on US abdomen, and 32 of these 49 patients underwent liver biopsy. RESULTS: Four of 32 (12.5%) individuals had steatosis alone. Mild, moderate and severe NASH was present in 21/32 (65.5%), 4/32 (12.5%) and 3/32 (9.35%), respectively. Fibrosis was present in 7/32 (21.8%) patients (four grade 1 and three grade 3). There was no significant difference in body mass index (BMI), transaminase levels, serum cholesterol and triglyceride levels among patients with non-alcoholic fatty liver disease. CONCLUSION: We conclude that the prevalence of NASH is high in type 2 DM patients and liver biopsy is the only investigation to differentiate between non-alcoholic fatty liver and steatohepatitis.     

Bone damage in type 2 diabetes mellitus

This review focuses on the mechanisms determining bone fragility in patients with type 2 diabetes mellitus (T2DM). Despite bone mineral density (BMD) is usually normal or more often increased in these patients, fracture incidence is high, probably because of altered bone ”quality”. The latter seems to depend on several, only partly elucidated, mechanisms, such as the increased skeletal content of advanced glycation end-products causing collagen deterioration, the altered differentiation of bone osteogenic cells, the altered bone turnover and micro-architecture. Disease duration, its severity and metabolic control, the type of therapy, the presence or absence of complications, as like as the other known predictors for falls, are all relevant contributing factors affecting fracture risk in T2DM. In these patients the estimate of fracture risk in the everyday clinical practice may be challenging, due to the lower predictive capacity of both BMD and risk factors-based algorithms (e.g. FRAX).     

Preventive pharmacotherapy in type 2 diabetes mellitus

Over the last few decades certain demographic changes have been observed worldwide, which have led to an increase in the prevalence of chronic non-communicable diseases. Type 2 diabetes mellitus and associated cardiovascular disease are major contributors to this disease burden leading to rising morbidity and mortality. It is worrisome to see that type 2 diabetes with its micro- and macrovascular complications is occurring in younger populations where it was hitherto unseen. Prevention appears to be an important strategy to reduce the burden of disease. Along with inculcating healthy lifestyle habits across populations, it may be suitable to use preventive pharmacotherapy in those with pre-diabetes and / or other risk factors like obesity, hypertension, and on the like. Metformin, alpha glucosidase inhibitors like acarbose, miglitol, and voglibose, and pioglitazone have all been used with success. The issues of compliance and adverse effects during long-term use have tempered the use of these drugs. The best approach would be to motivate the patient for effective lifestyle changes, and pharmacological management if the lifestyle changes are not successful in achieving their goals.     

Neuropsychiatric screening in type 2 diabetes mellitus

Diabetes mellitus is considered to be one of the most psychologically demanding of the chronic medical illnesses and is often associated with several psychiatric disorders. Psychiatric disorders can be a risk factor for, as well as a complication of, diabetes leading to bidirectional association between the two morbidities. Physicians caring for people with diabetes must be trained to recognize and manage comorbid psychiatric conditions that commonly occur. Our current article reviews the various screening procedures for effective evaluation of the neuropsychiatric illnesses coexisting with diabetes and other pertinent issues.     

Bone metabolism in type 2 diabetes mellitus

Several conditions have been described to cause osteoporosis, including diabetes mellitus. While the relationship between type 1 diabetes and osteopenia is well documented in the literature, data on the presence of this complication in type 2 diabetes have not been well established. We studied a population composed of 66 post-menopausal women with type 2 diabetes and a control population. We examined bone mineral density with the dual-energy X-ray absorptiometry (DXA) technique at the lumbar and femoral levels and, in a subgroup of patients, we also measured the levels of markers of bone remodelling. We found significantly higher levels of bone mineral density at the femoral (but not lumbar) level in the diabetic subjects compared with the control population in all the examined subregions, except Ward's triangle. Moreover, we found higher levels of some markers of bone resorption (urinary calcium and hydroxyproline, telopeptide) in the patients with diabetes, while urinary crosslinks were higher in the controls. On the basis of these results, we suggest that osteoporosis cannot be considered a complication of type 2 diabetes and that, from a metabolic point of view, bone resorption is greater in diabetic patients than in normal subjects, as suggested by the high levels of most of the markers of osteoclastic activity. Received: 16 March 1998 / Accepted in revised form: 24 February 1999