Insulin resistance and need for a lifestyle change to eliminate it.

The AIM of our work is to point out the relationship between insulin resistance and metabolic compensation of diabetes mellitus, as well as to explore the possibilities of improving these parameters by non-drug measures. The rising incidence of insulin resistance associated with many comorbidities, especially due to the increase in obesity and unhealthy lifestyles, is a serious medical problem today. It is therefore necessary to be able to recognize and evaluate the presence of insulin resistance, prevent its occurrence, and ensure its elimination in high-risk individuals. In our study, we evaluated 106 patients with diabetes mellitus based on glycated hemoglobin parameters, ratio of triacylglycerols to high-density lipoproteins, and body mass index before and after adjustment of dietary and regime measures. Statistical analysis of our data showed a positive correlation between the assessed parameters of insulin resistance and metabolic compensation of diabetes with a Pearson correlation coefficient of 0.3156, and a decrease in glycated hemoglobin and insulin resistance after adjustment of dietary and regimen measures in 73.58 % of patients. Based on the above results, it is shown that non-drug measures are able to significantly improve the parameters of metabolic compensation of diabetes mellitus as well as those of insulin resistance (Tab. 4, Fig. 1, Ref. 18) Keywords: insulin resistance, TAG/HDL ratio, diabetes mellitus.

Low risk of severe hypoglycaemia in patients with type 2 diabetes mellitus starting insulin therapy with premixed insulin analogues BID in outpatient settings.

AIMS: The choice of insulin at initiation in type 2 diabetes remains controversial. The aim of this study was to assess the occurrence of self-reported severe hypoglycaemia associated with premixed insulin analogues in routine clinical care. METHODS: A 12-month, prospective, observational, multicentre study in patients starting a commonly prescribed premixed insulin analogue (either insulin lispro 25/75 or biphasic insulin aspart 30/70, twice daily) after suboptimal glycaemic control on oral antidiabetic agents. Treatment decisions were made solely in the course of usual practice. RESULTS: Study follow-up was completed by 991 (85.5%) of the 1150 patients enrolled. At baseline, mean (SD) age was 57.9 (10.1) years; mean diabetes duration was 9.2 (5.9) years; mean haemoglobin A(1c) (HbA(1c)) was 9.9 (1.8) % and the rate of severe hypoglycaemia was 0.03 episode/patient-year. At 12 months, the rate of severe hypoglycaemia was 0.04 episode/patient-year (95% CI 0.023, 0.055 episode/patient-year) and mean insulin dose was 41.5 (19.4) units. Changes from baseline to 12 months for mean fasting plasma glucose and HbA(1c) were -5.1 mmol/l and -2.5%, respectively. CONCLUSIONS: After initiation of premixed insulin analogues in patients with type 2 diabetes in real-world settings, the incidence of severe hypoglycaemia was lower than expected from previously reported studies.

[Epidemiological characteristics of diabetes mellitus in Slovakia, 1992-2002]. / Epidemiologicke charakteristiky diabetes mellitus na Slovensku v rokoch 1992 az 2002.

UNLABELLED: Diabetes mellitus (DM) is one of the most important public health concerns and its consequences represent a considerable social and health burden. The study analyses the occurrence of DM in Slovakia in 1992-2002. MATERIAL AND METHODS: Age standardised incidence and prevalence rates of DM were calculated from the data published by the Institute of Health Information and Statistics for 1992, 1997 and 2002. Disease length and the incidence of selected complications in 1997 and 2002 were also analysed. RESULTS: In 1992-2002, DM prevalence in Slovakia increased from 4261.3 to 5065.8 cases per 100,000 population and appeared to be positively associated with age, while the DM incidence rates rose from 329.6 to 423.7 cases per 100,000 population. In most patients, DM length was 5 years or less, showing an upward trend over the studied period. From 1997 to 2002, the rates of selected diabetic complications slightly increased (from 18.7 % to 20.3 % for peripheral neuropathy, from 16.8 % to 18.0 % for retinopathy, from 7.1 % to 8.0 % for nephropathy and from 1.2 % to 1.3 % for amputations). DISCUSSION AND CONCLUSIONS: Comparing with the world data, Slovakia ranks among the countries with relatively high prevalence of DM, mainly due to the rising incidence. These results are consistent with the global upward trend in DM. However, taking into account underreporting, the actual DM prevalence in Slovakia could be considerably higher. Besides primary prevention, risk reduction measures should be focused particularly on early diagnosis and better implementation of secondary prevention.

[Latent autoimmune (type 1) diabetes mellitus in patients originally classified as type 2. Divergence of etiologic markers]. / Latentný autoimunitný (typ-1) diabetes mellitus u pacientov pôvodne klasifikovaných ako typ-2. Divergencia etiologických markerov.

BACKGROUND: To assess the prevalence of markers of autoimmune insulitis (AII) in patients classified originally as having Type-2 diabetes mellitus (Type-2 DM). 386 patients subdivided according to the BMI, C-peptide and type of treatment. METHODS AND RESULTS: Age, BMI, C-peptide, Glutamic acid decarboxylase autoantibodies (GADA), HLA-DR/,-DQ alleles. Prevalence of GADA varied from < 5% in obese patients with normal/increased C-peptide to > 30% in non-obese patients with low C-peptide. In majority of GADA positive patients, the Type-1 DM high-risk HLA-DRB1*, HLA-DQB1* alleles have been found. Among them HLA-DRB1*0302 and HLA-DRB1*0201 were more frequent than HLA-DRB1*040x and HL:A-DQB1*0302. CONCLUSIONS: Significant fraction of patients classified initially as Type-2 DM may have in fact Type-1 DM. Such patients can be recognized on the basis of assessment of serological (GADA) and immuno-genetical (HLA-DR/,-DQ alleles) markers. In some patients clinical, metabolic, immune, and immunogenetic markers may disagree. This divergence stresses multifactorial genesis of diabetes. Moreover, it can also suggest that both autoimmune insulitis and insulin resistance may coexist in parallel.

[Association of type I diabetes mellitus with HLA alleles]. / Asociácia diabetes mellitus I. typu s HLA-alelami.

Insulin-dependent diabetes mellitus is a chronic autoimmune disease characterised by a loss of tolerance towards own antigene structures beta-pancreatic cells. The destruction of cells subsequently leads to the loss of insulin production. There are more factors which trigger the autoimmune response in susceptible individuals, however, they are only partially known so far. One of the predisposing factors is the genotype, while the main role is ascribed to genes of the main histocompatible complex (HLA). Out of extensive genetic and epidemiological studies, the Caucasoid population is known to have a significant association of insulin-dependent diabetes mellitus with the increased frequencies of haplotypes HLA-DRB1*04-DQA1*0301-DQB1*0302 and DRB1*0301-DQA1*0501-DQB1*0201.

[Latent autoimmune (Type-1) diabetes mellitus in adults. Part. I. Serologic markers of autoimmune involvement of pancreatic beta-cells: GADA, ICA, IA-2 a IA-A]. / Latentný autoimunitný (Typ-1) diabetes mellitus u dospelých. I. Cast'. Sérologické markery autoimunitného postihnutia beta-buniek pankreasu: GADA, ICA, IA-2 a IA-A.

AIM OF STUDY: To assess the prevalence of markers of autoimmune destruction of pancreatic beta-cells (AIDbeta) in patients classified initially as Type-2 diabetes mellitus (Type-2 DM). SUBJECTS: 250 patients subdivided according to the: 1. BMI and C-peptide, 2. type of treatment. Measured parameters: age, BMI, C-peptide, autoantibodies directed against: glutamic acid decarboxylase (GADA), islet cells (ICA), thyrosinphosphatase (IA-2) and insulin (IA-A). RESULTS: GADA (and other AIDbeta markers) positivity varied from < 5% in patients with overweight/obesity (> 27 kg.m(-2)) and normal/increased C-peptide (> 0.32 nmol/l) to > 30% in non-obese patients with low C-peptide. CONCLUSION: Proportion of diabetics classified initially as having Type-2DM have had in fact slowly evolving autoimmune (Type-1) diabetes mellitus (LADA). In some patients both AID and insulin resistance may coexist in parallel. Pitfalls in interpretation of results of GADA, such as border positivity and similar, are discussed.

[Latent autoimmune (type I) diabetes mellitus in adults. Part. II. Association of HLA antigens, status of cellular immunity and occurrence of other autoimmune diseases]. / Latentný autoimunitný (Typ-1) diabetes mellitus u dospelých. II. Cast'. Asociácia s HLA antigénmi, stav bunkovej imunity a výskyt iných autoimunitných ochorení.

AIM OF STUDY: To assess some immunological and immunogenetic aspects in patients with latent autoimmune (Type-1) diabetes mellitus (DM) of adults (LADA). SUBJECTS: 24 patients with LADA, 11 patients with Type-2 DM and 20 healthy volunteers (Pilot study). PARAMETERS TESTED: HLA-DRB1* and HLA-DQB1* alleles, parameters of cellular immunity (CD4+, CD8+, CD3/HLA-DR+, CD8/HLA-DR+, CD45RA+[CD4], CD16+CD56), CD19+, IL-4, INF-gamma and organ specific (OSA) autoantibodies (against thyroid gland, gastric parietal cells, tubuli, basal membranes of glomerulus, AMA and ABBA). RESULTS AND DISCUSSION: Type-1 DM HLA-DRB1* and HLA-DQB1* risk alleles have been found in a majority of patients with LADA. The most frequent were HLA-DRB1*0301 and DQB1*0201. Assessement of parameters of cellular immunity and cytokine profiles (IL-4 a INF-gamma) in peripheral blood did not reveal any contribution to a differentiation between Type-1 and Type-2 DM). We confirmed increased occurence of OSA in patients with LADA, what stress importance of routine screening for OSA in patients with LADA.

[Glutamic acid decarboxylase autoantibodies (antiGAD-Ab) in patients with non-insulin dependent diabetes mellitus (NIDDM)]. / Autoprotilátky proti dekarboxyláze kyseliny glutámovej (antiGAD-Ab) u pacientov s non-inzulín dependentným diabetes mellitus (NIDDM).

AIM OF STUDY: To assess the prevalence of markers of autoimmune destruction of pancreatic beta-cells in patients with non-insulin dependent diabetes mellitus (NIDDM). SUBJECTS: 127 hospitalized NIDDM patients subdivided to the following subgroups: non-obese with C-peptide < 0.3 nmol/l (NIDDM-(-)), non-obese with C-peptide > 0.3 nmol/l (NIDDM-(+)), obese with C-peptide < 0.3 nmol/l (NIDDM+(-)) and obese with C-peptide > 0.3 nmol/l (NIDDM2+). METHODS AND MEASURED PARAMETERS: Age, BMI, C-peptide, autoantibodies to glutamic acid decarboxylase (antiGAD-Ab), autoantibodies to islet cells (ICA), markers of specific cellular immunity CD4, CD8, CD19, CD4/CD8, CD4/CD45/RA+, CD4/CD45/RA-, NK (CD16+56), CD3/HLADR, organ specific/non-specific autoantibodies. RESULTS: AntiGAD-Ab were positive in 5/15 (33.3%) NIDDM-(-), 1/32 (3.1%) NIDDM-(+), 2/9 (22.2%) NIDDM+(-) and in 3/71 (4.2%) NIDDM2+. The positivity of antiGAD-Ab in NIDDM-(-) and NIDDM+(-) was significantly higher (p < 0.05) than in NIDDM-(+) and NIDDM2+. CONCLUSION: Some patients with manifestation of diabetes in older age initially classified and treated as having NIDDM may have in fact slowly evolving autoimmune insulin-dependent diabetes mellitus (LADA). These patients can be identified by measurement of antiGAD-Ab or other markers (ICA, IA-2) of autoimmune destruction of pancreatic beta-cells (AID). Moreover, in some patients both AID and insulin resistance may coexist in parallel.

Endogenous digoxin-like immunoactivity in subjects with diabetes mellitus and hypertension.

The serum concentrations of digoxin-like immunoactivity (DLIA) were measured in 99 patients: 20 healthy volunteers (HV), 15 patients with insulin-dependent diabetes mellitus (IDDM), 14 patients with non-insulin-dependent diabetes mellitus without hypertension taking oral hypoglycemic (OHA) agents (NIDDM/-HT), 11 patients with NIDDM without hypertension taking insulin (NIDDM/-HT+INS), 12 NIDDM patients with hypertension taking OHA (NIDDM/+HT), nine NIDDM patients with hypertension taking insulin (NIDDM/+HT/+INS), 10 patients with essential hypertension with normal insulin levels (HT/-HI), and in eight patients with essential hypertension with hyperinsulinemia (HT/+HI). The numbers (%) of subjects with DLIA levels above the detection limit of the assay used (> 0.1 nmol/L) were, in the NIDDM/-HT group, 12/14 (85.7%) and in the NIDDM/+HT group, 9/12 (75%), significantly higher (P < .05) than in the HV (7/20; 35%), IDDM (3/15; 20%), and HT/-HI groups (2/10; 20%). The number and percentage of subjects with DLIA levels above the detection limit in the HT/+HI group was six of eight (75%), significantly (P < .05) higher than in the IDDM and HT/-HI groups, and tended to be higher than in the HV group (P < .055). Means and SD of serum DLIA levels (nmol/L) in the NIDDM/-EH (0.18/0.09) and NIDDM/+EH (0.19/0.15) groups were significantly higher (P < .05) than in the HV (0.09/0.07), IDDM (0.05/0.05), and EH/-HI (0.06/0.06) groups. DLIA levels in the HT/+HI group (0.15/0.12) were significantly higher (P < .05) than in the IDDM and HT/-HI groups. The percentage of DLIA levels above the detection limit, as well as the mean and SD of DLIA in the NIDDM group taking OHA, did not differ from those in subjects taking insulin. In all subjects studied (n = 99), DLIA correlated with C-peptide (r = 0.30; P < .01) and glomerular filtration (GF) (r = -0.21; P < .05). After exclusion of insulin-treated patients, DLIA correlated significantly with plasma glucose (PG; r = 0.25; P < .05), immunoreactive insulin (IRI; r = 0.41; P < .001), C-peptide (r = 0.27; P < .05), and GF (r = -0.26; P < .05) (n = 64). Correlation of DLIA with IRI (r = 0.33; P < .05; n = 38) also persisted after exclusion of patients taking insulin and those with DLIA levels below the detection limit. Similarly, DLIA also correlated with C-peptide (r = 0.64; P < .05) and IRI (r = 0.70; P < .05) in the subgroup of 10 patients with the highest levels of DLIA (> 0.25 nmol/L). None of the sera (n = 15) with different DLIA concentrations (0.0-0.38 nmol/L) exhibited K-pNPPase (Na+-K+-ATPase) inhibitory activity. In conclusion, this work demonstrated elevated serum DLIA in NIDDM and HT/+HI patients, and its correlation with IRI and GF. However, due to the fact that the chemical nature and biologic properties of DLIA are still a matter of debate, it is too early to speculate whether the elevation of DLIA is just a secondary result associated with HI and reduced GF, or whether it also has pathophysiologic consequences. Nevertheless, in both cases the elevated concentrations of substances with DLIA and their interference with antidigoxin antibodies may affect therapeutic monitoring of digitalization in NIDDM and HT/+HI patients. Also, the elevated DLIA could subclassify these patients. The significance of such subclassifications (pathophysiologic, therapeutic, or prognostic), however, will need further investigation.

[Insulin antibodies in patients with type 2 diabetes mellitus]. / Protilátky proti inzulínu (IA-A) u pacientov s diabetes mellitus Typ-2.

AIM OF STUDY: To assess the prevalence of insulin antibodies (IA-A) and their binding capacity (c%IA-A) in Type-2 diabetic patients and relation of IA-A/c%IA-A to duration of diabetes, type of therapy, kind/dosage of administered insulin, glycaemic control and to appearance of hypoglycaemic episodes. SUBJECTS: 196 hospitalised patients with type-2 diabetes mellitus (negative for antiGAD-Ab). Assessed parameters: age, duration of diabetes mellitus, duration of insulin-therapy, BMI, glycaemic profile, IRI, C-peptide, IA-A and antiGAD-Ab (Cis bio international, distr. fy Solupharm). RESULTS: Prevalence of IA-A and their c%IA-A were related to treatment with insulin. c%IA-A correlated significantly with fasting plasma glucose and IRI concentrations. c%IA-A did not correlate with insulin dosages, C-peptide, BMI, nor with age. CONCLUSION: Prevalence of IA-A and their c%IA-A in patients with Type-2 diabetes affects levels of total plasma insulin, insulin kinetic and consequently the quality of glycaemic compensation. Prevalence of IA-A is related to duration of insulin therapy, but independent on dosage of administered insulin.

[Tissue plasminogen activator and diabetes mellitus]. / Tkanivový aktivátor plazminogénu (tPA) a diabetes mellitus.

tPA has been the independent risk factor of the thrombosis associated with atherosclerosis. There are increased tPA levels in type 1 diabetic patients with vascular complications and tPA is endothelial injury marker in this case. In type 2 diabetes mellitus elevated tPA antigen levels in early disease stage are caused by increased production of complexes with inhibitor (PAI-1) and tPA or fibrinolytic activity has been decreased.

Endogenous digoxin-like immunoactivity and diabetes mellitus: facts and hypotheses.

Substances with digoxin- and ouabain-like immunoactivity (DLIA) are specific inhibitors of Na(+)-K(+)-ATPase which increase the total amount of intracellular stored calcium (Ca2+i). In diabetic patients, DLIA levels have been reported to be increased. Although this increase is probably secondary to sodium retention and volume expansion (included in diabetic subjects by hyperinsulinemia and/or diabetic nephropathy), the question arises of whether it has pathophysiological consequences: namely, whether substances with DLIA, via their effect on Na(+)-K(+)-ATPase activity and Ca2+i stores, could in diabetic subjects facilitate development of hypertension and/or modulate insulin sensitivity or insulin secretion. Clinical findings of correlations of DLIA to blood pressure, insulin levels and to degree of insulin resistance, together with experimental findings of decreased Na(+)-K(+)-ATPase activity, increased Ca2+i and decreased Mg2+i in both diabetic and hypertensive subjects, support these hypotheses. However, the issue of whether or not these relations are causative and whether or not defects in intracellular milieu are primary or secondary to non-insulin-dependent diabetes mellitus has not been resolved yet. Moreover, pathogenesis of both diabetes mellitus and hypertension is multifactorial and includes many other factors. Therefore, further efforts should be made to elucidate the exact role of substances with DLIA in diabetes mellitus.

Endothelial markers in diabetes mellitus.

In this study we examined 22 NIDDM patients without vascular complications and 17 age-matched healthy blood donors. Von Willebrand factor (vWF) levels were significantly increased in NIDDM patients compared to healthy blood donors (1.33 +/- 0.39 vs 1.01 +/- 0.27 IU/ml p = 0.006), while thrombomodulin (TM) levels were similar in the both groups. vWF levels correlated with calcium dependent secretion parameters such as C-peptide (r = 0.680, p < 0.001) and PF4 (r = 0.613, p < 0.01) and did not correlate with calcium-independent markers of endothelial injury such as TM (r = 0.287, p = 0.196) and TFPI (r = 0.296, p = 0.181). Therefore it seems that increased levels of Cai-dependent endothelial and platelet activation markers may precede the signs of endothelial damage. This hypothesis requires further research.

[What does the relation of digoxin-like immunoactivity and serum insulin levels in pregnant women signify?]. / Co signalizuje vztah digoxínu podobnej imunoaktivity k hladinám inzulínu v sére tehotných zien?

BACKGROUND: Digoxin-like immunoactivity (DLIA) reflects the presence of endogenous substances which are close to cardiac glycosides. These substances via inhibition of Na(+)-K(+)-ATPase increase intracellular calcium stores (Ca2+i) and may modulate various Ca(2+)-dependent mechanisms. Although DLIA are known primarily as hypertension and natriuresis promoting factors, several recent works have suggested that DLIA relates also to diabetes mellitus. The main stimulus for DLIA secretion represents volume-expansion. AIM OF STUDY: To assess relation of DLIA to glucose tolerance and insulin levels in pregnant women (PW). SUBJECTS AND METHODS: 1) 67 PW (DLIA measured by RIA-kit HUMA-LAB Kosice), 2) 53 PW (DLIA measured by RIA-kit ORION). PW were subdivided according to the glucose tolerance and insulin concentrations. RESULTS: 1. DLIA in hyperinsulinemic PW were significantly higher than in those with normal insulin levels. 2. DLIA significantly correlated with insulin levels as well as with insulinogenic index. 3. The increase in plasma glucose and insulinemia during OGTT was accompanied by a decrease in DLIA. These findings were independent of other measured parameters (age, body mass index, pregnancy induced weight gain, blood pressure and steroid hormones). CONCLUSIONS: These findings suggest that DLIA does not respond only to changes regarding sodium-retention and volume-expansion, but also to changes in glucose and insulin metabolism. Thus, DLIA could represent one of the markers of "specific" neurohumoral activation. However, the question of whether an elevation in DLIA may consequently modulate mechanisms of insulin secretion, insulin sensitivity, vascular reactivity and other Ca2+i-dependent mechanisms remains speculative. (Tab. 4, Fig. 4, Ref. 41).

[Plasminogen activator inhibitor (PAI-1) and markers of endothelial dysfunction in patients with diabetes mellitus]. / Inhibítor aktivátora plazminogénu (PAI-1) a markery dysfunkcie endotelu u chorých s diabetes mellitus.

The authors examined 25 patients with diabetes mellitus type 2 (NIDDM) without vascular complications, treated by sulphonyl urea preparations, 12 hyperinsulinaemic (HI) non-diabetic subjects and 11 normoinsulinaemic healthy subject s. Patients with NIDDM and HI non-diabetics had significantly elevated PAI-1 levels which correlated with the C-peptide level (r = 0.519, p < 0.001), triacylglycerols (TG) (r = 0.685, p < 0.001), BMI (r = 0.607, p < 0.001) and levels of endothelial markers such as von Willebrand s factor and thrombomodulin (TM). In the group of patients with NIDDM no relationship of PAI-1 and C-peptide was found and a significant correlation was found with TM levels (r = 0.609, p = 0.001) and TG levels (r = 0.476, p = 0.046). The results suggest that the endothelial department has an effect on the regulation of PAI-1 levels in patients with NIDDM.

[Hemostasis in patients with diabetes mellitus. II. Tissue factor and the extrinsic blood coagulation inhibitor]. / Hemostáza u chorých s diabetes mellitus. II. Tkanivový faktor a inhibítor vonkajsieho systému koagulácie.

In the submitted pilot study we examined 37 patients suffering from diabetes mellitus without vascular complications and 15 healthy blood donors. The diabetic patients had not, as compared with the blood donors, significantly elevated values of the tissue factor (TF) and tissue factor pathway inhibitor (TFPI). The TFPI levels correlated with other markers of endothelial dysfunction, in particular thrombomodulin (r = 0.452, p < 0.01) and with triacylglycerol and cholesterol levels. They did not correlate with age, the C-peptide level and BMI.

[Hemostasis in patients with diabetes mellitus. I. Markers of endothelial dysfunction]. / Hemostáza u chorých s diabetes mellitus. I. Markery dysfunkcie endotelu.

In the submitted pilot study the authors examined 47 diabetic patients without vascular complications and 15 healthy blood donors. In an aged-matched sub-group the authors confirmed significantly elevated levels of Willebrand factor (vWF) in patients with non-insulin dependent diabetes mellitus (NIDDM), as compared with healthy blood donors, while the thrombomodulin (TM) levels did not differ significantly. The mutual correlation of parameters with calcium-dependent release (vWF, platelet factor PF4 and C-peptide) was confirmed in the group of patients with NIDDM with normal TM values and in the group of blood donors. These findings could be explained by the hypothesis that raised intracellular calcium levels, described already in early stages of diabetes could in diabetic patients participate also in the activation of haemostasis.

[Insulin resistance and pathogenesis of non-insulin-dependent diabetes mellitus (part II)]. / Inzulínová rezistencia a patogenéza non-inzulín-dependentného diabetes mellitus (II.cast').

A review of the existing views is given, focused on the role of insulin resistance (IR), impaired insulin secretion and reduced suppression of hepatic glucose output and in the pathogenesis of noninsulin dependent diabetes mellitus (NIDDM). Currently, there are two basic theories on the sequence of these defects. Most of the authors suggest that NIDDM is caused primarily by insulin resistance (IR) (which is also considered an earliest detectable defect) with subsequent inability of the pancreas sufficiently compensate for IR. However, some authors suggest that NIDDM results from the abnormal pancreatic beta-cell function (disturbed pulsatility and first-phase of stimulated insulin secretion). These authors consider IR a secondary defect. It seems, that both these theories are well founded. Actually NIDDM is not a single disorder but is rather a syndrome of diverse etiology and pathogenesis. In case of NIDDM with obesity the primary etiopathogenetic role can be rather ascribed to IR. while in non-obese NIDDM subjects the secretory defect is more probable as a primary cause.