Effect of a multicomponent intervention on achievement and improvements in quality-of-care indices among people with Type 2 diabetes in South Asia: the CARRS trial.

AIMS: To evaluate whether and what combinations of diabetes quality metrics were achieved in a multicentre trial in South Asia evaluating a multicomponent quality improvement intervention that included non-physician care coordinators to promote adherence and clinical decision-support software to enhance physician practices, in comparision with usual care. METHODS: Using data from the Centre for Cardiometabolic Risk Reduction in South Asia (CARRS) trial, we evaluated the proportions of trial participants achieving specific and combinations of five diabetes care targets (HbA1c <53 mmol/mol [7%], blood pressure <130/80 mmHg, LDL cholesterol <2.6 mmol/L, non-smoking status, and aspirin use). Additionally, we examined the proportions of participants achieving the following risk factor improvements from baseline: ≥11-mmol/mol (1%) reduction in HbA1c , ≥10-mmHg reduction in systolic blood pressure, and/or ≥0.26-mmol/l reduction in LDL cholesterol. RESULTS: Baseline characteristics were similar in the intervention and usual care arms. Overall, 12.3%, 29.4%, 36.5%, 19.5% and 2.2% of participants in the intervention group and 16.2%, 38.3%, 31.6%, 11.3% and 0.8% of participants in the usual care group achieved any one, two, three, four or five targets, respectively. We noted sizeable improvements in HbA1c , blood pressure and cholesterol, and found that participants in the intervention group were twice as likely to achieve improvements in all three indices at 12 months that were sustained over 28 months of the study [relative risk 2.1 (95% CI 1.5,2.8) and 1.8 (95% CI 1.5,2.3), respectively]. CONCLUSIONS: The intervention was associated with significantly higher achievement of and greater improvements in composite diabetes quality care goals. However, among these higher-risk participants, very small proportions achieved the complete group of targets, which suggests that achievement of multiple quality-of-care goals is challenging and that other methods may be needed in closing care gaps.

Biallelic PDX1 (insulin promoter factor 1) mutations causing neonatal diabetes without exocrine pancreatic insufficiency.

AIMS: Recessive PDX1 (IPF1) mutations are a rare cause of pancreatic agenesis, with three cases reported worldwide. A recent report described two cousins with a homozygous hypomorphic PDX1 mutation causing permanent neonatal diabetes with subclinical exocrine insufficiency. The aim of our study was to investigate the possibility of hypomorphic PDX1 mutations in a large cohort of patients with permanent neonatal diabetes and no reported pancreatic hypoplasia or exocrine insufficiency. METHODS: PDX1 was sequenced in 103 probands with isolated permanent neonatal diabetes in whom ABCC8, KCNJ11 and INS mutations had been excluded. RESULTS: Sequencing analysis identified biallelic PDX1 mutations in three of the 103 probands with permanent neonatal diabetes (2.9%). One proband and his affected brother were compound heterozygotes for a frameshift and a novel missense mutation (p.A34fsX191; c.98dupC and p.P87L; c.260C>T). The other two probands were homozygous for novel PDX1 missense mutations (p.A152G; c.455C>G and p.R176Q; c.527G>A). Both mutations affect highly conserved residues located within the homeobox domain. None of the four cases showed any evidence of exocrine pancreatic insufficiency, either clinically, or, where data were available, biochemically. In addition a heterozygous nonsense mutation (p.C18X; c.54C>A) was identified in a fourth case. CONCLUSIONS: This study demonstrates that recessive PDX1 mutations are a rare but important cause of isolated permanent neonatal diabetes in patients without pancreatic hypoplasia/agenesis. Inclusion of the PDX1 gene in mutation screening for permanent neonatal diabetes is recommended as a genetic diagnosis reveals the mode of inheritance, allows accurate estimation of recurrence risks and confirms the requirement for insulin treatment.

Insulinoma--a case report.

Insulinoma is a rare pancreatic endocrine tumour characterised by hyperinsulinemic hypoglycemia. It is important to surgically remove this tumour as it can cause potentially lethal hypoglycemia. We report a case of insulinoma presenting with unconsciousness following repeated episodes of inability to arise from sleep and convulsions. Biochemical investigation revealed hypoglycemia and hyperinsulinemia. The diagnosis of Insulinoma is often delayed due to misattribution of symptoms to psychiatric or neurological disorders. In this case, same delay lead to fatal outcome for this patient.

Acanthosis nigricans: a dermatologic marker of metabolic disease.

Most patients with acanthosis nigricans have either clinical or subclinical insulin resistance. We undertook a study to estimate the insulin sensitivity of a group of patients referred from the dermatologist with biopsy proven acanthosis nigricans. Thirty-six patients were evaluated in the Endocrinology clinic. Plasma glucose and serum Insulin levels were estimated after a 75 gms oral glucose load (OGTT). An intravenous Insulin Tolerance Test (ITT) was performed with measurement of Glucose Disposal Rate (GDR). There were 28 females and 8 males (M:F--3.5:1; mean age 26.3+/-1.7 years) in the study. 25/36 patients were morbidly obese (BMI--36.0 +/- 1.2 Kg/m2) with an abnormal body fat distribution (WH ratio--0.9 +/ - 0.02). One patient had generalized lipoatrophy. 16/36 patients with acanthosis nigricans had IGT or overt diabetes and all had highly significant hyperinsulinemia (AUCI = 20825 +/ 1287.7 vs. 6340.0 +/- 984.2 mIU/ml/hr in controls, p < 0.0005). The GDR in patients with acanthosis nigricans was reduced (-0.66 +/- 0.07) compared to controls (-0.39 +/- 0.08; p < 0.01). There was a significant positive correlation between indices of adiposity and insulin resistance in subjects with impaired tolerance.

A study of insulin resistance in subjects with acanthosis nigricans.

AIM: To study the prevalence of insulin resistance (IR) and its sequelae in patients with acanthosis. METHODOLOGY: Thirty six patients (28 females; eight males) with biopsy proven acanthosis nigricans and eight controls were evaluated for insulin sensitivity (IS) by estimating (a) the glucose and insulin responses to a 75 gm glucose load (Oral glucose tolerance test-OGTT), (b) the glucose disposal rate (GDR) during an intravenous insulin tolerance test (ITT). Serum androgen levels (testosterone--Te, androstenedione--ASD, Dehydro-epiandrosterone sulphate--DHEAS) were estimated in the basal state and 60 min after a bolus of insulin. Thyroid function tests (tri-iodo-thyronine--T3, thyroxine--T4, thyroid stimulating hormone--TSH) were performed in all subjects. RESULTS: The acanthotic population, overall had insignificant hyperglycemia (Area under curve of glucose--AUC-G : 17,745.5 +/- 847.5 v/s 11,051.3 +/- 274.5 mg/dl/min) and hyperinsulinemia (Area under curve of insulin -AUC-I: 20,825.2 +/- 1,287.7 v/s 6,340.1 +/- 984.2 microlU/ml/min) compared to controls during OGTT. Eight patients with acanthosis nigricans had impaired glucose tolerance and eight had overt diabetes using WHO criteria. 69.4% of the acanthotic subjects were obese and 13.9% (5/36) were hypertensive. Thyroid dysfunction was present in three (one had hypothyroidism and two had thyrotoxicosis). Reproductive disorders--menstrual irregularity (46.5%), amenorrhea (21.4%), hirsuitism (21.4%) and infertility (3.6%) was encountered in a significant number of acanthotics. Acanthotics overall had statistically higher levels of androgens; Te (females)--0.74 +/- 0.09 v/s 0.27 +/- 0.09 ng/ml (p < 0.005), ASD--1.8 +/- 0.21 v/s 0.94 +/- 0.2 ng/ml (p < 0.005) and DHEAS--1,880.8 +/- 216.3 v/s 772.8 +/- 210.4 ng/ml (p < 0.005). An elevated DHEAS correlated positively to body mass index (BMI) and android obesity. Serum Te levels correlated positively with GDR. Serum insulin levels increased progressively with obesity and acanthosis. Serum insulin was associated with progressive worsening of hyperandrogenism (as seen in non-obese controls, non-obese and obese acanthotics). CONCLUSIONS: Subjects with acanthosis nigricans should be screened for insulin resistance and its clinical and metabolic sequelae. Thyroid dysfunction should be sought in these subjects as it can be easily treated.

Microalbuminuria in insulin dependent diabetes mellitus.

This study aimed to evaluate the prevalence of microalbuminuria (MAU) and albumin excretion rate (AER) in a timed overnight (12 hours) urine sample, in 72 insulin-dependent-diabetic (IDD) patients and to correlate the same to the clinical profile, glycemic control and to diabetic complications. Nine IDD patients (prevalence--12.5%) were detected to be microalbuminuric. Males had significantly higher prevalence of MAU (17.4%) than females (3.8%; p < 0.05). The prevalence of MAU was 4% in the third decade of age, 15% each in the fourth and fifth and 28.6% and 60% in the sixth decade and above (p < 0.05%). Prevalence of MAU also increased progressively with duration of diabetes. It increased from 8.3% (< 5 yrs) to 12.5% (6-10 yrs) and 33.3% (> 15 yrs). High AER in obese patients--33.1 +/- 23.2 v/s 11.4 +/- 3.4 micrograms/min in lean patients supports an association of obesity with albuminuria. Higher prevalences of MAU (62.5%; p < 0.001) was observed in hypertensive IDD patients in comparison to normotensive patients (3.6%). AER in patients with borderline hypertension (21.0 +/- 14.5 micrograms/min; p < 0.05) and in overt hypertensives (49.1 +/- 19.2 micrograms/min; p < 0.0005) were significantly higher compared to normotensive IDD-patients (6.2 +/- 2.4 micrograms/min). Prevalence of MAU and AER increased progressively with the deterioration of glycemic control. Well controlled subjects were normoalbuminuric. The incidence of MAU increased from 11.1% in fairly controlled (NS) and 21.1% in poorly controlled (p < 0.01) subjects. Also AER increased significantly from 2.4 +/- 0.5 micrograms/min. to 9.8 +/- 6.7 and 23.1 +/- 7.3 micrograms/min with the deterioration of glycemic control. Glycemic control in terms of glycated hemoglobin (GHb) did not show much agreement with the prevalence of MAU and AER, though they worsened with deteriorating control. The prevalences of peripheral neuropathy (PN) (34.4% v/s 33.3%) and diabetic retinopathy (DR) (9.8% v/s 11.1%) were similar in normo- and microalbuminuric patients. Patients with PN had high AER (15.2 +/- 6.3 micrograms/min). Also, AER was significantly high in patients with DR (27.7 +/- 23.5 micrograms/min; p < 0.05). High prevalences of cardio-vascular disease (CVD) (33.3%; p < 0.05) were observed in microalbuminuric compared to normoalbuminuric (1.6%) patients. Also AER was significantly high in association with CVD (53.9 +/- 21.9 micrograms/min; p < 0.0005). It can be concluded that, in IDD patients, MAU is common in males, older individuals and subjects with longer duration of diabetes. Raised blood pressure and hyperglycemia were identified as risk factors for the development of MAU.

Microalbuminuria in non-insulin dependent diabetes mellitus.

Non-insulin-dependent diabetes mellitus (NIDDM) is the commonest form of diabetes. The aim of this study was to evaluate the nature and prevalence of microalbuminuria (MAU) in NIDDM. One hundred and twenty-eight NIDDM patients participated in this study on the prevalence of microalbuminuria and albumin excretion rate (AER). An attempt was made to correlate them to the clinical profile, glycemic control and to diabetic complications. Eighteen patients had MAU with 14.1% prevalence (males--17.5% v/s females--10.8%; NS). Prevalence of MAU was higher in the third and fourth decades of age (28.6%) with a decrease in the fifth decade (12.5%). Prevalence of MAU also increased progressively with duration of diabetes--13 to 14% (< 10 yrs) to 25% (> 10 yrs). High AER in obese patients (13.4 +/- 5.5 v/s 7.9 +/- 1.4 micrograms/min) supports an association of obesity with albuminuria. The prevalence of MAU in patients with borderline and overt hypertension was not statistically different from that in normotensive NIDDM patients. However, NIDDM with borderline hypertension showed high AER 16.2 +/- 5.6 micrograms/min compared to 7.8 +/- 1.3 micrograms/min in normotensives. Prevalence to MAU and AER increased progressively with the deterioration of glycemic control--from 3.3% in well controlled to 18.9% in fairly controlled (P < 0.5) and 31% in poor controlled patients (P < 0.01). Also AER increased significantly from 3.9 +/- 0.8 to 12.3 +/- 4.1 and 18.4 +/- 4.6 micrograms/min, in patients with well to fairly and poorly controlled glycemia respectively. The prevalence of MAU and AER did not correlate with glycated hemoglobin (GHb) levels. The prevalences of peripheral neuropathy (PN) (42.6% v/s 55.6%) were similar in normo- and microalbuminuric patients. Patients with PN had high AER 11.9 +/- 2.7 micrograms/min. Diabetic retinopathy (DR) was equally prevalent in normo- and microalbuminuric NIDDM patients of (20.4% v/s 22.2), and AER was not significantly higher (12.1 +/- 4.3 micrograms/min) in NIDDM with retinopathy. High prevalences of cardiovascular disease (CVD) in MAU-NIDDM (22.2%; NS) was observed compared to normoalbuminuric (9.3%) patients. Also AER was significantly high in NIDDM associated with CVD (21.9 +/- 10.9 micrograms/min; P < 0.025). It can be concluded that, MAU is more prevalent in third and fourth decades and with longer duration of diabetes. Poor glycemic control was identified as a risk factor as in IDDM for development of MAU. MAU was a marker of generalised vascular dysfunction.

Prevalence of islet cell antibodies and its correlation with glucose and insulin response to oral glucose tolerance test in 1st degree relatives of insulin dependent diabetes mellitus probands.

93 first degree relatives (1st DR) of insulin dependent diabetes mellitus (IDDM) patients were investigated for detection of islet cell antibodies (ICA) and beta cell functional status. ICA were detected in 26.9% Ist DR subjects (25/93), equally in parents, siblings and offspring. Normal (n = 16), impaired (n = 5) and diabetic (n = 4), glucose curves were seen in 1st DR. Low insulin levels were observed in parents and siblings with normal glucose tolerance test (N-GTT) at 90 min (p < 0.05), and (p < 0.0005) relatives with impaired glucose tolerance and diabetes. Insulin release to glucose (IRG-insulinogenic index) in control group was 352 +/- 42 mu U/mg. From the group of 25 ICA positive cases, 4 had mean IRG of 394 +/- 70 mu U/mg (group A) comparable to control, and had N-GTT; 12 had mean IRG of 107 +/- 15.9 mu U/mg (group B) significantly low (P < 0.005) compared to controls and group A and 9 showed IRG of 75 +/- 29.3 mu U/mg, lower than group B (NS) with abnormal response to glucose load. Loss of insulin secretory ability thus can precede hyperglycemia by years. The ICA positive relatives were grouped based on the immunological status with their probands. ICA status in probands does not give an idea about ICA status in their relatives. This indepth study leads to understand the correlation of genetic, metabolic and immunological parameters for early detection of IDDM in first degree relatives.

Prevalence of islet cell antibodies and B cell functional status in insulin dependent diabetes.

As autoimmunity is an important factor in the etiopathogenesis of IDDM, 85 ketosis prone i.e. insulin dependent diabetes (IDD) were evaluated for immunological and beta cell functional status. Islet cell antibodies (ICA) against purified islet cells used in Microwell ELISA Method, were detected in 27.1% of cases (23/85). There was a prevalence of 36.4% of ICA positivity in newly diagnosed cases and its prevalence declined with duration. The highest ICA positivity was observed in fourth decade of life. 17 of the 23 ICA positive cases (73.9%) had a mean duration of 2.1 years whereas the remaining 6/23 (26.1%) had a mean duration of 9 years. Females showed a younger age of onset of diabetes. Only one female with duration of 10 years tested positive for ICA.ICA positive males had later age of onset and longer duration of diabetes as compared to ICA positive females. Ten ICA positive cases studied were showing non-significant C-peptide (CP) release (after glucose load) in comparison to negative cases (14); p < 0.05, 8 of these cases were with < 3 months duration. Significantly low delta % C-peptide response implies a low residual beta-cell function and further loss of beta cell function earlier in ICA +ve cases. Thus this study leads to understand in depth the immune mechanism of IDDM.

Endocrine profiles in six patients with acanthosis nigricans.

Six women (age range 17-38 years), who presented to the dermatology services with biopsy-proven acanthosis nigricans of variable duration were evaluated to rule out endocrine diseases. Menstrual abnormalities (5/6 patients), pallid striae (4/6 patients), hirsutism (4/6 patients) and acne vulgaris (2/6 patients) were found on physical examination. All the patients had body mass indices in the obese (> 27 kg/m2) range, and in association we found ovarian hyperthecosis, PCOD, premature ovarian failure, glucose intolerance and hyperprolactinaemia in the above six patients. The importance of appropriate endocrinal evaluation in patients with biopsy-proven acanthosis nigricans is emphasized.

C-peptide profiles in young diabetics.

Fifty-six patients who had been diagnosed diabetic prior to the age of 30 were evaluated to determine the C-peptide (CP) secretory response to a glucose load. These individuals were classified clinically as having insulin dependent (IDDM = 18); non-insulin dependent (NIDDM = 19) and insulin requiring diabetes (IRDM = 19). Insulin dependent diabetics had lower basal CP levels (0.44 +/- (SE) 0.1 ng/ml) which were not stimulated by hyperglycaemia (0.55 +/- 0.13 ng/ml) as compared to controls (basal CP = 1.6 +/- 0.2 and peak 6.2 +/- 0.8 ng/ml). Non-insulin dependent diabetics and insulin requiring diabetics could be divided broadly into two groups - one, a set of patients with low basal CP levels (NIDDM = 0.63 +/- 0.09 ng/ml) (IRDM = 0.38 +/- 0.08 ng/ml) and a blunted response to a glucose load (peak response NIDDM = 0.83 +/- 0.05 ng/ml, IRDM = 0.59 +/- 0.12 ng/ml) and a second group who had CP reserve evident in both fasting (NIDDM = 1.6 +/- 0.2 ng/ml; IRDM = 2.1 +/- 0.6) and post-glucose levels (Peak Response NIDDM = 4.6 +/- 0.4 ng/ml; IRDM = 3.0 +/- 0.6 ng/ml). Growth Hormone (GH) and cortisol levels were found to be high in patients with IDDM and IRDM with no insulin reserve and these did not suppress during the oral Glucose Tolerance Test. NIDDM patients with no insulin reserve had normal GH and high cortisol levels. It is emphasized from this study that insulin sensitivity is as important as the insulin secretory status in determining the presenting features of diabetes mellitus in the young.

Macroglossia--the presenting feature of primary amyloidosis.

A case of amyloidosis with macroglossia as a presenting feature is described. The patient was diagnosed to have multiple myeloma at least 1 1/2 year after amyloidosis was diagnosed.

Gemfibrozil in familial and type V hyperlipidaemias. Report of 3 cases.

Gemfibrozil, a lipid lowering agent, was administered to two patients with familial hyperlipidaemia and one patient with insulin dependent diabetes mellitus. It was partially effective in familial hyperlipidaemia. It dramatically reduced triglyceride and cholesterol levels in the patient with Type V hyperlipidaemia and insulin dependent diabetes mellitus. Patients with familial and Type V hyperlipidaemias should be given a trial of gemfibrozil therapy.

Amyotrophy in young diabetics: clinical profiles.

Seven young patients presenting with diabetic amyotrophy, unusual at their age, are described. Besides symptoms suggestive of proximal muscle weakness and occasionally of diabetes, all patients were underweight; abdominal pain occurred in all the patients. The diagnosis of amyotrophy was confirmed on electromyography and nerve conduction studies in all patients, and muscle biopsy in two patients. All patients recovered fully on control of diabetes with insulin. Only two episodes of stress induced ketosis were recorded in these 7 patients. These patients were not ketotic though they were severely uncontrolled on omission of insulin. They had normal lipid levels, and had no other complications of diabetes. Pancreatic calculi were found in only one patient. We describe here the clinical profiles of these patients and discuss the possible aetiologies of diabetes and the clinical implications.

Gemfibrozil in hyperlipidaemia: an open, single blind trial.

The efficacy of Gemfibrozil on S. lipid levels was studied in 36 middle aged subjects with type IIA, IIB, IV hyperlipidemia. Gemfibrozil was well tolerated in the dose of 1200 mg/day and no dropouts were attributable to its use. An overall reduction in total cholesterol (39.91%), total triglycerides (71.10%), VLDL triglycerides (62.97%). LDL cholesterol (45.57%) and apolipoprotein B levels (26.83%) were observed at 24 weeks. At the same time HDL cholesterol, and apolipoprotein A levels showed increases by 26.23% and 53.67% respectively. It is concluded that Gemfibrozil is an effective lipid lowering agent. Further long term studies are necessary to determine its optimal dosage and its long term safety in Indian subjects.