Normalization of fasting glycaemia by intravenous GLP-1 ([7-36 amide] or [7-37]) in Type 2 diabetic patients

Intravenous GLP-1 [7-36 amide] can normalize fasting hyperglycaemia in Type 2 diabetic patients. Whether GLP-1 [7-37] has similar effects and how quickly plasma glucose concentrations revert to hyperglycaemia after stopping GLP-1 is not known. Therefore, 8 patients with Type 2 diabetes (5 female, 3 male; 65 ± 6 years; BMI 34.3 ± 7.9 kg m⁻²; HbA_1c 9.6 ± 1.2 %; treatment with diet alone (n = 2), sulphonylurea (n = 5), metformin (n = 1)) were examined twice in randomized order. GLP-1 [7-36 amide] or [7-37] (1 pmol kg⁻¹min⁻¹) were infused intravenously over 4 h in fasted subjects. Plasma glucose (glucose-oxidase), insulin and C-peptide (ELISA) was measured during infusion and for 4 h thereafter. Indirect calorimetry was performed. Fasting hyperglycaemia was 11.7 ± 0.9 [7-36 amide] and 11.3 ± 0.9 mmol l⁻¹ [7-37]. GLP-1 infusions stimulated insulin secretion approximately 3-fold (insulin peak 168 ± 32 and 156 ± 47 pmol l⁻¹, p < 0.0001 vs basal; C-peptide peak 2.32 ± 0.28 and 2.34 ± 0.43 nmol l⁻¹, p < 0.0001, respectively, with GLP-1 [7-36 amide] and [7-37]). Four hours of GLP-1 infusion reduced plasma glucose (4.8 ± 0.4 and 4.6 ± 0.3 mmol l⁻¹, p < 0.0001 vs basal values), and it remained in the non-diabetic fasting range after a further 4 h (5.1 ± 0.4 and 5.3 ± 0.4 mmol l⁻¹, for GLP [7-36 amide] and [7-37], respectively). There were no significant differences between GLP-1 [7-36 amide] and [7-37] (glucose, p = 0.99; insulin, p = 0.99; C-peptide, p = 0.99). Neither glucose oxidation nor lipid oxidation (or any other parameters determined by indirect calorimetry) changed during or after the administration of exogenous GLP-1. In conclusion, GLP-1 [7-36 amide] and [7-37] normalize fasting hyperglycaemia in Type 2 diabetic patients. Diabetes therapy (diet, sulphonyl ureas or metformin) does not appear to influence this effect. In fasting and resting patients, the effect persists during administration of GLP-1 and for at least 4 h thereafter, without rebound. Significant changes in circulating substrate concentrations (e.g. glucose) are not accompanied by changes in intracellular substrate metabolism. © 1998 John Wiley & Sons, Ltd.     

Effects of subcutaneous glucagon-like peptide 1 (GLP-1 [7–36 amide]) in patients with NIDDM

Summary Intravenous glucagon-like peptide (GLP)-1 [7–36 amide] can normalize plasma glucose in non-insulin-dependent diabetic (NIDDM) patients. Since this is no form for routine therapeutic administration, effects of subcutaneous GLP-1 at a high dose (1.5 nmol/kg body weight) were examined. Three groups of 8, 9 and 7 patients (61 ± 7, 61 ± 9, 50 ± 11 years; BMI 29.5 ± 2.5, 26.1 ± 2.3, 28.0 ± 4.2 kg/m²; HbA_{1 c} 11.3 ± 1.5, 9.9 ± 1.0, 10.6 ± 0.7 %) were examined: after a single subcutaneous injection of 1.5 nmol/kg GLP [7–36 amide]; after repeated subcutaneous injections (0 and 120 min) in fasting patients; after a single, subcutaneous injection 30 min before a liquid test meal (amino acids 8 %, and sucrose 50 g in 400 ml), all compared with a placebo. Glucose (glucose oxidase), insulin, C-peptide, GLP-1 and glucagon (specific immunoassays) were measured. Gastric emptying was assessed with the indicator-dilution method and phenol red. Repeated measures ANOVA was used for statistical analysis. GLP-1 injection led to a short-lived increment in GLP-1 concentrations (peak at 30–60 min, then return to basal levels after 90–120 min). Each GLP-1 injection stimulated insulin (insulin, C-peptide, p < 0.0001, respectively) and inhibited glucagon secretion (p < 0.0001). In fasting patients the repeated administration of GLP-1 normalized plasma glucose (5.8 ± 0.4 mmol/l after 240 min vs 8.2 ± 0.7 mmol/l after a single dose, p = 0.0065). With the meal, subcutaneous GLP-1 led to a complete cessation of gastric emptying for 30–45 min (p < 0.0001 statistically different from placebo) followed by emptying at a normal rate. As a consequence, integrated incremental glucose responses were reduced by 40 % (p = 0.051). In conclusion, subcutaneous GLP-1 [7–36 amide] has similar effects in NIDDM patients as an intravenous infusion. Preparations with retarded release of GLP-1 would appear more suitable for therapeutic purposes because elevation of GLP-1 concentrations for 4 rather than 2 h (repeated doses) normalized fasting plasma glucose better. In the short term, there appears to be no tachyphylaxis, since insulin stimulation and glucagon suppression were similar upon repeated administrations of GLP-1 [7–36 amide]. It may be easier to influence fasting hyperglycaemia by GLP-1 than to reduce meal-related increments in glycaemia. [Diabetologia (1996) 39: 1546–1553]     

alpha-Glucosidase inhibition (acarbose) fails to enhance secretion of glucagon-like peptide 1 (7-36 amide) and to delay gastric emptying in Type 2 diabetic patients.

AIM: Acarbose is able to enhance GLP-1 release and delay gastric emptying in normal subjects. The effect of alpha-glucosidase inhibition on GLP-1 has been less evident in Type 2 diabetic patients. The aim of this study was to investigate the possible influence of acarbose on GLP-1 release and gastric emptying in Type 2 diabetic patients after a mixed test meal. PATIENTS AND METHODS: Ten Type 2 diabetic patients were tested with 100 mg acarbose or placebo served with a mixed meal that was labelled with 100 mg 13C-octanoic acid. Plasma concentrations of glucose, insulin, C-peptide, glucagon, GLP-1 and GIP were determined over 6 h. Gastric emptying was measured by determining breath 13CO2 using infrared absorptiometry. Statistics repeated-measures anova. RESULTS: Gastric emptying rates (t1/2: 162 +/- 45 vs. 163 +/- 62 min, P = 0.65) and plasma concentrations (increasing from approximately 12 to approximately 25 pmol/l, P = 0.37) and integrated responses of GLP-1 (P = 0.37) were not changed significantly by acarbose treatment. Postprandial plasma glucose concentrations (P < 0.0001) and their integrated responses were lowered by acarbose (by 64%; P = 0.016). The plasma concentrations of insulin and C-peptide were reduced (P = 0.007 and 0.057, respectively) by acarbose, while glucagon was not changed (P = 0.96). GIP plasma concentrations (increasing with placebo from approximately 10 to approximately 85 pmol/l and with acarbose to approximately 55 pmol/l (P < 0.0001) and their integrated responses were significantly lowered (by 43%) by acarbose (P = 0.021). After 2 weeks of acarbose treatment (50 mg t.i.d. for the first and 100 mg t.i.d. for the second week, n = 6), similar results were found. CONCLUSIONS: In hyperglycaemic Type 2 diabetic patients, ingestion of acarbose with a mixed test meal failed to enhance GLP-1 release and did not influence gastric emptying.     

Prolonged and enhanced secretion of glucagon-like peptide 1 (7-36 amide) after oral sucrose due to α-glucosidase inhibition (acarbose) in Type 2 diabetic patients

GLP-1, an incretin hormone of the enteroinsular axis with insulinotropic and glucagonostatic activity, is secreted after nutrient ingestion. GLP-1 is mainly produced by intestinal L-cells in the lower gastrointestinal tract (GIT); simple carbohydrates are absorbed in the upper GIT and α-glucosidase inhibition leads to augmented and prolonged GLP-1 release in normal subjects. In a cross-over study, 100 mg acarbose or placebo was administered simultaneously with 100 g sucrose to 11 hyperglycaemic Type 2 diabetic patients poorly controlled with diet and sulphonylureas. Plasma levels of GLP-1, insulin, C-peptide, glugacon, GIP, glucose and H₂-exhalation were measured over 6 h. Differences in the integrated responses over the observation period were evaluated by repeated measurement analysis of variance with fasting values used as covariates. With acarbose, sucrose reached the colon 60–90 min after ingestion as indicated by a significant increment in breath hydrogen exhalation (p = 0.005). After an early GLP-1 increment 15 min after sucrose under both conditions, GLP-1 release was prolonged in the acarbose group (p = 0.001; significant from 210 to 360 min). Initially (0–150 min), glucose (p = 0.001), insulin (p = 0.001), and GIP (p<0.001) were suppressed by acarbose, whereas later there were no significant differences. Glucagon levels were higher with acarbose in the last 3 h of the 6 h observation period (p = 0.02). We conclude that in hyperglycaemic Type 2 diabetic patients, ingestion of acarbose with a sucrose load leads to elevated and prolonged GLP-1 release. © 1998 John Wiley & Sons, Ltd.     

Insulinotropic actions of intravenous glucagon-like peptide-1 (GLP-1) [7–36 amide] in the fasting state in healthy subjects

GLP-1 (7–36 amide) stimulates insulin and suppresses glucagon secretion in normal subjects and may, in pharmacological doses, normalize hyperglycaemia in type 2 diabetic patients. It is not known whether such pharmacological doses can actually lower blood glucose to hypoglycaemic levels. Therefore, in seven normal fasting subjects, GLP-1 (7–36 amide) was infused intravenously at 0.3, 0.9 and 2.7 pmol/kg per min for 30 min each. The plasma concentration of GLP-1 (7–36 amide) increased dose-dependently, but insulin secretion (insulin, C-peptide) was stimulated only marginally. Glucagon was slightly suppressed, and plasma glucose was reduced, but not into the hypoglycaemic range. In conclusion, when plasma glucose concentrations are in the normal fasting range, GLP-1 (7–36 amide) is not able to stimulate insulin secretion to a degree that causes hypoglycaemia. This should limit the risk of hypoglycaemic responses when GLP-1 (7–36 amide) is administered in pharmacological doses to reduce hyperglycaemia in type 2 diabetic patients.     

Subclinical diabetic neuropathy: similarities between electrophysiological results of patients with Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetes mellitus

Summary Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetic patients share many clinical and biochemical characteristics. However, sural nerve biopsies from patients with advanced and chronic neuropathy show ultrastructural differences between these two groups. We investigated whether at a subclinical stage of the illness, when Type 1 and Type 2 diabetic patients are clinically uniform and the histopathological nerve alterations are not advanced, comparison between the two diabetes groups might show differences in nerve fibre involvement related to the different pathogeneses of the neuropathies. A total of 88 diabetic patients (52 Type 1 and 36 Type 2), with a subclinical form of polyneuropathy were selected. The clinical neurophysiological examination consisted of motor and sensory nerve conduction studies, Hoffmann (H)-reflex, single fibre electromyography and static as well as dynamic pupillometry. With regard to clinical neurophysiological abnormalities, the severity of the polyneuropathy appeared to be equal in both groups. Despite the absence of clinical symptoms the neurophysiological abnormalities were pronounced and it was impossible to differentiate Type 1 diabetic patients from Type 2 diabetic patients on a clinical neurophysiology basis when correcting for differences in age, height, and duration of illness. In the Type 1 diabetic group as well as in the Type 2 diabetic group the autonomic nerve fibres and nerves in the legs were more frequently affected than the thick myelinated nerves in the arms. These findings do not support the assumption that there is a difference in the manifestation of polyneuropathy between Type 1 and Type 2 diabetic patients.     

Comparison of the course to end-stage renal disease of Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetic nephropathy

Summary Is the course leading to diabetic end-stage renal disease similar for Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetes mellitus? We identified all diabetic end-stage renal disease patients starting renal replacement therapy from 1989 to 1991 in two urban counties in Texas. Three ethnic/racial groups were enrolled: Mexican Americans, non-Hispanic Whites, African Americans. Patients were interviewed and their medical records, both inpatient and out-patient, were abstracted for relevant diagnostic and therapeutic information. We attempted to obtain records as far back as the onset of diabetes or hypertension and from all physicians who had cared for the patient. An historical algorithm was used to determine diabetic type. Of the patients enrolled, 91 were Type 1 and 438 were Type 2 diabetic patients. Type 1 diabetic patients had higher mean glucose levels in the first 10 years of diabetes (16.3 vs 11.4 mmol/l) but lower systolic blood pressures (148 vs 157 mmHg). The duration of diabetes prior to end-stage renal disease was longer for Type 1 than Type 2 patients (22 vs 17 years). Type 1 diabetic patients were more likely to have other microvascular complications (retinopathy, neuropathy, gastroparesis), less likely to have coronary disease (myocardial infarction and congestive heart failure), and had similar rates of stroke and vascular surgery procedures (carotid endarterectomy, coronary artery bypass surgery, aortofemoral bypass). Type 1 and Type 2 diabetic patients were just as likely to have a first degree relative with hypertension (60.5 vs 65.5%). The late manifestations of end-stage renal disease were similar between the two groups (kidney size, proteinuria, slope of the inverse of creatinine, laboratory data prior to end-stage renal disease, reasons for starting dialysis). The course to end-stage renal disease may be different for Type 1 and Type 2 diabetes, with hyperglycaemia playing a more dominant role in Type 1 and hypertension playing a more dominant role for Type 2. The Type 1/Type 2 differences in patterns of other diabetic complications add weight to this hypothesis. However, the late course of the renal disease and the end result on the kidney is very similar.     

Relationship of progressively increasing albuminuria to apoprotein(a) and blood pressure in Type 2 (non-insulin-dependent) and Type 1 (insulin-dependent) diabetic patients

Summary This study has explored the temporal relationship between apoprotein(a), blood pressure and albuminuria over a mean interval of 11 years in a cohort of 107 diabetic patients of whom 26 (14 Type 2 (non-insulin-dependent), 12 Type 1 (insulin-dependent) had progressively increasing albuminuria (‘progressors’). In Type 2 diabetic patients, no significant differences were noted for HbA₁, blood pressure, creatinine clearance or serum lipids between progressors and non-progressors. In Type 1 diabetic patients, final systolic and diastolic blood pressures were higher in progressors compared with non-progressors and progressors showed impairment of renal function in association with a rise in blood pressure at the macroalbuminuric stage. Initial apoprotein(a) levels were similar in progressors and non-progressors of either diabetes type. Apoprotein(a) levels increased exponentially with time in 12 of 14 Type 2 progressors but only in 5 of 12 Type 1 progressors (p<0.01). In Type 2 diabetic patients, the annual increase in apoprotein(a) levels was 9.1±2.4%, which was significantly greater than in non-progressors, 2.0±1.2% (p<0.01) and also exceeded the rates of increase of apoprotein(a) in progressors with Type 1 diabetes, 4.0±1.4%, (p<0.05). Apoprotein(a) levels correlated significantly with albuminuria in 8 of 14 Type 2 progressors but only in 3 of 12 Type 1 progressors (p<0.05). The rate of increase of apoprotein(a) levels was not related to mean HbA₁, creatinine or creatinine clearance levels, or to albuminuria. The rate of rise of apoprotein(a) was not influenced by initial apoprotein(a) levels, suggesting that specific apoprotein(a) isoforms do not influence albuminuria-related increases in apoprotein(a). The data are consistent with the hypothesis that apoprotein(a) levels increase in response to albuminuria and may be part of a self-perpetuating process. This study also suggests that increases in apoprotein(a) levels commence during the microalbuminuria stage in diabetic patients, which is earlier than has been documented in non-diabetic proteinuria.     

The course of kidney function in Type 2 (non-insulin-dependent) diabetic patients with diabetic nephropathy

Summary We evaluated the impact of some putative progression promoters on kidney function in albuminuric Type 2 (non-insulin-dependent) diabetic patients with biopsyproven diabetic glomerulosclerosis. Twenty-six patients (1 female) with a mean age of 52 (standard error 2) years and a known mean duration of diabetes of 9 (1) years were followed-up prospectively for a mean of 5.2 (range 1.0–7.0) years. Twenty-one patients received antihypertensive treatment. During the observation period the glomerular filtration rate decreased from 83 (24–146) to 58 (2–145) ml·min⁻¹·1.73 m⁻² (mean (range)) (p<0.001). The mean rate of decline in glomerular filtration rate was 5.7 (−3.5 to 22.0) ml/min per year. Albuminuria increased from 1.2 (0.3–7.2) to 2.3 (0.4–8.0) g/24 h (geometric mean (range)) (p<0.001). Arterial blood pressure remained unchanged: 162/93 (SE 4/3) and 161/89 (4/2) mm Hg. Univariate analysis showed the rate of decline in glomerular filtration rate to correlate with systolic blood pressure (r=0.71,p<0.001), mean blood pressure (r=0.56,p<0.005), albuminuria (r=0.58,p<0.005) and the initial glomerular filtration rate (r=−0.49,p<0.02). The rate of decline in glomerular filtration rate did not correlate significantly with dietary protein intake, total cholesterol, high-density lipoprotein cholesterol or HbA_1c. Three patients died from uraemia and four patients died from cardiovascular disease. Two patients required renal replacement therapy at the end of the observation period. Our prospective observational study revealed that one-fifth of the patients developed end-stage renal failure during the 5-year observation period. The decline in glomerular filtration rate varied considerably between patients. Increase in arterial blood pressure to a hypertensive level is an early feature of diabetic nephropathy. Elevated systolic blood pressure accelerates the progression of diabetic nephropathy in Type 2 diabetic patients.     

Plasma apolipoprotein (a) is increased in Type 2 (non-insulin-dependent) diabetic patients with microalbuminuria

Summary Patients with Type 2 (non-insulin-dependent) diabetes mellitus complicated by microalbuminuria or albuminuria, have an increased risk of developing macrovascular disease and of early mortality. Because lipoprotein abnormalities have been associated with diabetic nephropathy, this study tested the hypothesis that levels of apolipoprotein (a) are elevated in patients with Type 2 diabetes and increased levels of urinary albumin loss. Levels of apolipoprotein (a) in diabetic patients with microalbuminuria (n = 26, geometric mean 195 U/1, 95 % confidence interval 117–324) and albuminuria (n = 19, 281 U/1,165–479) were higher than in non-diabetic control subjects (n = 140,107 U/1, 85–134,p < 0.05), and in the albuminuric group than diabetic patients without urinary albumin loss (n = 58, 114 U/1, 76–169,p < 0.05). Patients with microalbuminuria and albuminuria had levels comparable with patients undergoing elective coronary artery graft surgery (n = 40,193 U/1,126–298). Apolipoprotein (a) levels were higher in diabetic patients with macrovascular disease than in those without (n = 49, 209 U/1, 143–306 vsn = 54, 116 U/1, 78–173,p < 0.05). These preliminary results suggest that raised apolipoprotein (a) levels of Type 2 diabetic patients with microalbuminuria and albuminuria may contribute to their propensity to macrovascular disease and early mortality.     

Effects of glucagon-like peptide-1 (7-36)amide on insulin stimulated rat skeletal muscle glucose transport

Glucagon-like peptide-1 binding sites have been reported in peripheral tissues including muscle. However, the potential extra-pancreatic effects of glucagon-like peptide-1(7-36)amide are controversial. To evaluate whether glucagon-like peptide-1(7-36)amide has any effects on skeletal muscle glucose transport, isolated rat soleus muscles were incubated in increasing concentrations of insulin (0–150 nmol/l) in the presence or absence of 1 nmol/l glucagon-like peptide-1(7-36)amide for 3 h. Subsequently glucose transport was measured as uptake of [³H]-O-methylglucose. It was found that glucagon-like peptide-(7-36)amide has a small but significant stimulating effect on skeletal muscle glucose transport independent of the insulin concentration (P<0.01). However, because of the magnitude of the observed effect, the physiological importance of glucagon-like peptide-1 (7-36)amide on skeletal muscle glucose metabolism is questionable. Received: 27 February 1998 / Accepted in revised form: 30 April 1998     

Reduced incretin effect in Type 2 (non-insulin-dependent) diabetes

Summary Integrated incremental immunoreactive insulin and connecting peptide responses to an oral glucose load of 50 g and an “isoglycaemic” intravenous glucose infusion, respectively, were measured in 14 Type 2 (non-insulin-dependent) diabetic patients and 8 age- and weight-matched metabolically healthy control subjects. Differences between responses to oral and intravenous glucose administration are attributed to factors other than glucose itself (incretin effect). Despite higher glucose increases, immunoreactive insulin and connecting peptide responses after oral glucose were delayed in diabetic patients. Integrated responses were not significantly different between both groups. However, during “isoglycaemic” intravenous infusion, insulin and connecting peptide responses were greater in diabetic patients than in control subjects as a consequence of the higher glycaemic stimulus. The contribution of incretin factors to total insulin responses was 72.8 ± 6.9% (100% = response to oral load) in control subjects and 36.0 ± 8.8% in diabetic patients (p ≦ 0.05). The contribution to connecting peptide responses was 58.4 ± 7.6% in control subjects and 7.6 ± 14.5% (p ≦ 5 0.05) in diabetic patients. Ratios of integrated insulin to connecting peptide responses suggest a reduced (hepatic) insulin extraction in control subjects after oral as compared to intravenous glucose. This was not the case in diabetic patients. Immunoreactive gastric inhibitory polypeptide responses were not different between control subjects and diabetic patients. A reduced or lost incretin effect in the face of normal gastric inhibitory polypeptide response in Type 2 diabetic patients may be explained by decreased sensitivity of the B cells towards the insulinotropic effect of gastric inhibitory polypeptide or to hyposecretion or reduced effectiveness of as yet unidentified humoral or nervous gut factors with incretin activity.     

A genetic study of retinopathy in South Indian Type 2 (non-insulin-dependent) diabetic patients

Summary Genetic marker studies in diabetic retinopathy are controversial and frequently complicated by possible independent associations of Type 1 (insulin-dependent) diabetes mellitus with the markers so far analysed. We have looked for associations of candidate genes with retinopathy in South Indian Type 2 (non-insulin-dependent) diabetic patients; patients were subdivided into those with exudative maculopathy (n=53), proliferative retinopathy (n=40) and patients free from diabetic retinopathy with a minimum disease duration of 15 years (n=45). DNA was extracted from blood samples and studied by Southern blot hybridisation techniques and the following probe enzyme combinations: HLA-DQB1; Taq 1, HLA-DQA1; Taq 1, HLA-DRA; Bgl II, insulin gene hypervariable region; Pvu II and the switch region of the immunoglobulin IgM heavy chain gene (S); Sac I. Differences in genotype distributions between the study groups were only detected with the S probe which detects polymorphism of both S and S1 (the switch region of IgA). Two alleles of S1 were detected sized 7.4 kilobase and 6.9 kilobase. The frequency of 6.9 kilobase homozygotes was lower in proliferative retinopathy (19%) compared to patients free from diabetic retinopathy (54%, p=0.005) and exudative maculopathy (46%, p=0.03). This data suggests that there is a genetic predisposition to proliferative retinopathy in Type 2 (non-insulin-dependent) diabetes of South Indian origin and that this is determined by polymorphism of the heavy chain immunoglobulin genes located on chromosome 14.     

Linkage analysis of the glucokinase locus in familial Type 2 (non-insulin-dependent) diabetic pedigrees

Summary Glucokinase is among the few genes which may play a key role in both insulin secretion and insulin action. Glucokinase is present in pancreatic beta cells where it may have a key role in the glucose sensing mechanism, and it is present in hepatocytes, where it may participate in glucose flux. Glucokinase defects have recently been implicated in maturity-onset diabetes of the young. To examine the hypothesis that glucokinase plays a key role in the predisposition to common familial Type 2 (non-insulin-dependent) diabetes mellitus, we typed 399 members of 18 Utah pedigrees with multiple Type 2 diabetic individuals for two markers in the 5 and 3 flanking regions of the glucokinase gene. Linkage analysis was performed under both dominant and recessive models. We also repeated these analyses with individuals with impaired glucose tolerance who were considered affected if their stimulated (2-h) glucose exceeded age-specific normal levels for 95 % of the population. Under several dominant models, linkage was significantly excluded, and under recessive models log of the odds (LOD) score was less than –1. We were also unable to demonstrate statistical support for the hypothesis that a small subgroup of pedigrees had glucokinase defects, but the most suggestive pedigree (individual pedigree LOD 1.8–1.9) ranked among the youngest and leanest in our cohort. We can exclude a major role for glucokinase in familial Type 2 diabetes, but our data cannot exclude a role for this locus in a minority of pedigrees. Further testing of the hypothesis that glucokinase defects contribute to diabetes in a small proportion of Type 2 diabetic pedigrees must await thorough sequence analysis of the glucokinase gene, including regulatory regions, particularly from pedigrees with positive LOD scores.     

Insulin resistance in Type 2 (non-insulin-dependent) diabetic patients with hypertriglyceridaemia

Summary Hypertriglyceridaemia, which is frequently seen in Type 2 (non-insulin-dependent) diabetes mellitus, is associated with insulin resistance. The connection between hypertriglyceridaemia and insulin resistance is not clear, but could be due to substrate competition between glucose and lipids. To address this question we measured glucose and lipid metabolism in 39 Type 2 diabetic patients with hypertriglyceridaemia, i. e. mean fasting serum triglyceride level equal to or above 2 mmol/l (age 59±1 years, BMI 27.4±0.5 kg/m², HbA_1c8.0±0.2%, serum triglycerides 3.2±0.2 mmol/l) and 41 Type 2 diabetic patients with normotriglyceridaemia, i. e. mean fasting serum triglyceride level below 2 mmol/l (age 58±1 years, BMI 27.0±0.7 kg/m², HbA_1c7.8±0.2 %, serum triglycerides 1.4±0.1 mmol/l). Insulin sensitivity was assessed using a 340 pmol·(m²)^–1· min^–1 euglycaemic insulin clamp. Substrate oxidation rates were measured with indirect calorimetry and hepatic glucose production was estimated using a primed (25 Ci)-constant (0.25 Ci/min) infusion of [3-³H]-glucose. Suppression of lipid oxidation by insulin was impaired in patients with hypertriglyceridaemia vs patients with normal triglyceride levels (3.5±0.2 vs 3.0±0.2mol·kg^–1· min^–1; p<0.05). Stimulation of glucose disposal by insulin was reduced in hypertriglyceridaemic vs normotriglyceridaemic patients (27.0±1.3 vs 31.9±1.6 mol·kg^–1·min^–1; p<0.05) primarily due to impaired glucose storage (9.8±1.0 vs 14.6±1.4mol·kg^–1·min^–1; p<0.01). In contrast, insulinstimulated glucose oxidation was similar in patients with hypertriglyceridaemia and in patients with normal triglyceride concentrations (16.9±0.8 vs 17.2±0.7mol·kg^–1·min^–1). Hepatic glucose production in the basal state and during the clamp did not differ between the two groups. We conclude therefore that oxidative substrate competition between glucose and lipids does not explain insulin resistance associated with hypertriglyceridaemia in Type 2 diabetes. The question remains whether the reduced nonoxidative glucose disposal observed in the patients with hypertriglyceridaemia is genetically determined or a consequence of increased lipid oxidation.     

Shared genetic susceptibility of Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetes mellitus: contributions of HLA and haptoglobin

Summary Epidemiologic data suggest that having a parent with Type 2 (non-insulin-dependent) diabetes mellitus increases the risk for Type 1 (insulin-dependent) diabetes in siblings of a Type 1 diabetes proband. This increase in risk is consistent with a shared genetic susceptibility between Type 1 diabetes and Type 2 diabetes. We contrast genetic risk factors in three sets of families, consisting of (1) a single Type 1 diabetic child (proband) and non-diabetic parents, (2) multiple Type 1 diabetic siblings and non-diabetic parents, and (3) at least one Type 1 diabetic child and at least one Type 2 diabetic parent. Previous studies have demonstrated that HLA region genes, which elevate the risk in Type 1 diabetes, have no significant effect with respect to the risk for developing Type 2 diabetes. An earlier report cited a contribution by the haptoglobin locus to genetic susceptibility for Type 2 diabetes. We provide evidence that a high risk HLA antigen (HLA-DR3) is decreased to a greater extent in Type 1 patients with a Type 2 parent than in Type 1 patients in which the parents are not diabetic. The role of HLA-DR4 is maintained in these families, with an unexpectedly significant increased rate of transmission of the HLA-DR4 allele from Type 2 parent to Type 1 offspring. The role of haptoglobin in these families does not appear to be important, either with respect to association with diabetes or with respect to linkage with a secondary susceptibility locus. These results indicate that families with a Type 2 parent and Type 1 child, heavily determined by HLA-DR4 linked factors, may represent a homogeneous subset of diabetes susceptibility.     

Apolipoprotein(a) and cardiovascular disease in Type 2 (non-insulin-dependent) diabetic patients with and without diabetic nephropathy

Summary The relative mortality from cardiovascular disease is on average increased five-fold in Type 2 (non-insulin-dependent) diabetic patients with diabetic nephropathy compared to non-diabetic subjects. We assessed the possible contribution of dyslipidaemia in general and elevated serum apolipoprotein(a) (apo(a)) in particular. Type 2 diabetic patients with normo-, micro- and macroalbuminuria were compared with healthy subjects. Each group consisted of 37 subjects matched for age, sex and diabetes duration. Serum creatinine in the nephropathy group was 105 (54–740) mol/l. The prevalence of ischaemic heart disease (resting ECG, Minnesota, Rating Scale) was 57, 35, 19 and 2% in macro-, micro- and normoalbuminuric diabetic patients and healthy subjects, respectively. The prevalence of ischaemic heart disease was higher in all diabetic groups as compared to healthy subjects (p<0.05), and higher in macroalbuminuric as compared to normoalbuminuric diabetic patients (p<0.01). There was no significant difference between apo(a) in the four groups: 161 (10–1370), 191 (10–2080), 147 (10–942), 102 (10–1440) U/l (median (range)) in macro-, micro- and normoalbuminuric groups and healthy subjects. Serum total-cholesterol, HDL-cholesterol and LDL-cholesterol were not significantly different when comparing healthy subjects and each diabetic group. Apolipoprotein A-I was lower (p<0.05) in all diabetic groups as compared to healthy subjects (nephropathy vs healthy subjects): 1.50±0.25 vs 1.69±0.32 g/l (mean ± SD). Triglyceride was higher (p<0.05) in patients with nephropathy and microalbuminuria as compared to healthy subjects (nephropathy vs healthy subjects): 2.01 (0.66–14.7) vs 1.09 (0.41–2.75) mmol/l (median (range)). Apolipoprotein B was higher (p<0.02) in patients with nephropathy as compared to the other three groups (nephropathy vs healthy subjects): 1.54±0.47 vs 1.33±0.30 g/l. In conclusion, our case-control study has confirmed that Type 2 diabetic patients with increased urinary albumin excretion frequently suffer from dyslipidaemia and cardiovascular disease. However, our study revealed no significant elevation in serum concentration of apo(a) in patients with diabetic nephropathy, but numbers were small.     

Counterregulation in Type 2 (non-insulin-dependent) diabetes mellitus. Normal endocrine and glycaemic responses,up to ten years after diagnosis

Summary We have examined hormonal and metabolic responses to insulin-induced hypoglycaemia in 10 Type 2 (non-insulin-dependent) diabetic patients treated with tablets and 10 age, sex and weight matched control subjects. Diabetic patients were under 110% ideal body weight, had no autonomie neuropathy and were well controlled (HbA₁, 7.1±0.2%). After the diabetic patients were kept euglycaemic by an overnight insulin infusion, hypoglycaemia was induced in both groups by intravenous insulin at 30 mU·m^–2·min^–1 for 60 min and counterregulatory responses measured for 150 min. There were no significant differences between diabetic patients and control subjects in the rate of fall (3.3±0.3 vs 4.0±0.3 mmol·1^–1·h^–1), nadir (2.4±0.2 vs 2.3±0.1 mmol/l) and rate of recovery (0.027±0.002 vs 0.030±0.003 mmol·1^–1·min^–1) of blood glucose. Increments of glucagon (60.5±5.7 vs 70±9.2 ng/l) and adrenaline (1.22±0.31 vs 1.45±0.31 nmol/l) were similar in both groups. When tested using this model, patients with Type 2 diabetes, without microvascular complications and taking oral hypoglycaemic agents show no impairment of the endocrine response and blood glucose recovery following hypoglycaemia.     

Coronary heart disease and urinary albumin excretion rate in Type 2 (non-insulin-dependent) diabetic patients

Summary Associations between overnight urinary albumin excretion rate and prevalent coronary heart disease and its major risk factors were examined in a cross-sectional study of 141 Type 2 (non-insulin-dependent) diabetic patients. Mean albumin excretion rate was higher in men (geometric mean 13.5 g/min; 95% confidence interval 10.3–17.6) than women (7.5 g/min; 5.7–9.8, p<0.01). In diabetic men and women mean albumin excretion rate was higher in those with electrocardiographic and/or symptomatic evidence of coronary heart disease than in those without (men, 23.1 g/ min; 95% confidence interval 13.7–39.0 versus 10.6 g/min; 7.9–14.2, p<0.01, women, 13.7 g/min; 8.0–23.5 versus 5.4 g/min; 4.2–6.8, p<0.01). Multiple logistic regression analysis was used to allow for confounding between variables. In the diabetic group as a whole, raised albumin excretion rate (p<0.001), gender (p<0.05) and systolic blood pressure (p=0.06) entered the best model for coronary heart disease prediction. In women, albumin excretion rate alone (p<0.01) and in men albumin excretion rate (p<0.01) and age (p=0.05) entered the best models. We conclude that albumin excretion rate is significantly associated with coronary heart disease morbidity after taking into account the confounding effects of raised blood pressure and other cardiovascular risk factors.     

Lowering of triglycerides by gemfibrozil affects neither the glucoregulatory nor antilipolytic effect of insulin in Type 2 (non-insulin-dependent) diabetic patients

Summary Hypertriglyceridaemia and insulin resistance are closely associated but it is unknown whether hypertriglyceridaemia per se contributes to insulin resistance. In the present study we examined whether gemfibrozil, by lowering triglyceride levels, improves the glucoregulatory and antilipolytic action of insulin in Type 2 (non-insulin-dependent) diabetes mellitus. Twenty patients were randomly allocated to receive either placebo or gemfibrozil 1200 mg daily for 12 weeks in a double-blind study. Very low density lipoprotein triglyceride levels decreased in the gemfibrozil group by 42±12% (p<0.01). Gemfibrozil had no effect on the diurnal concentration of non-esterified fatty acids (NEFA). At the randomization HbA_1c levels were comparable (7.6±0.3 vs 7.8±0.2%, NS) and increased slightly both in the gemfibrozil (8.2±0.4%, p<0.05) and placebo groups (8.0±0.3%, NS). Pre- and post-treatment diurnal glucose and insulin concentrations remained unchanged. Basal pre- and post-treatment hepatic glucose production rates were comparable in both groups and similarly suppressed by insulin. Rate of whole body glucose disposal during a low-dose insulin infusion (serum insulin 90 pmol/l) (pre- vs post-gemfibrozil 11.9±1.1 vs 11.1±0.7, pre- vs post-placebo 9.9±1.1 vs 10.8±0.8 mol·kg^–1·min^–1, NS for both) and a high-dose insulin infusion (serum insulin 500 pmol/l) (16.2+-1.7 vs 17.7±2.7, 17.1±4.2 vs 17.4±2.9 mol·kg^–1·min^–1, respectively, NS for both) remained unchanged. Basal pre- and post-treatment NEFA turnover rates were comparable in both groups and similarly suppressed by insulin. Also rates of total lipid oxidation, plasma NEFA oxidation and non-oxidative NEFA metabolism remained unchanged in both groups. We conclude that gemfibrozil effectively lowers serum triglycerides but has no effect on insulin sensitivity of glucose and NEFA metabolism. The data suggest that hypertriglyceridaemia is a consequence rather than a cause of insulin resistance in Type 2 diabetic patients.