Prevention of Type 2 (non-insulin-dependent) diabetes mellitus by diet and physical exercise The 6-year Malmö feasibility study

Summary From a previously reported 5-year screening programme of 6,956 47–49-year-old Malmö males, a series of 41 subjects with early-stage Type 2 (non-insulin-dependent) diabetes mellitus and 181 subjects with impaired glucose tolerance were selected for prospective study and to test the feasibility aspect of long-term intervention with an emphasis on life-style changes. A 5-year protocol, including an initial 6-months (randomised) pilot study, consisting of dietary treatment and/or increase of physical activity or training with annual check-ups, was completed by 90% of subjects. Body weight was reduced by 2.3–3.7% among participants, whereas values increased by 0.5–1.7% in non-intervened subjects with impaired glucose tolerance and in normal control subjects (p<0.0001); maximal oxygen uptake (ml · min^–1 · kg^–1) was increased by 10–14% vs decreased by 5–9%, respectively (p<0.0001). Glucose tolerance was normalized in > 50% of subjects with impaired glucose tolerance, the accumulated incidence of diabetes was 10.6%, and more than 50% of the diabetic patients were in remission after a mean follow-up of 6 years. Blood pressure, lipids, and hyperinsulinaemia were reduced and early insulin responsiveness to glucose loading preserved. Improvement in glucose tolerance was correlated to weight reduction (r=0.19, p<0.02) and increased fitness (r=0.22, p<0.02). Treatment was safe, and mortality was low (in fact 33% lower than in the remainder of the cohort). We conclude that long-term intervention in the form of diet and physical exercise is feasible even on a large scale, and that substantial metabolic improvement can be achieved which may contribute to prevent or postpone manifest diabetes.     

Primary prevention of Type 2 (non-insulin-dependent) diabetes mellitus

Summary Type 2 (non-insulin-dependent) diabetes mellitus is the major form of the disease in all societies. Its public health impact appears to be increasing and the greatest genetic predisposition to the disease is encountered in developing communities. The reduction or elimination of disease in whole populations is a fundamental goal in public health. Whilst several factors are associated with the development of Type 2 diabetes, it is not clear how they cause the disease, if indeed they do, nor whether they act in the same way in all populations. Risk factors may be true determinants of a disease but alternatively they may be associated with its occurrence only by virtue of an innocent relationship with the true causes. Furthermore, known risk factors usually explain only a small proportion of any chronic disease. The role of risk factors in disease causation is therefore of fundamental importance in considering disease prevention. Two alternative strategies for prevention of disease in populations have been proposed. The population strategy seeks to remove the causes of disease in communities as a whole, whilst the high-risk strategy aims to identify subjects at increased risk, and to intervene selectively. The population approach should be tried and carefully evaluated in selected communities at above-average risk of several noncommunicable diseases. However, certain epidemiological features of Type 2 diabetes, including the distributional characteristics of glycaemia and the complications of hyperglycaemia, the clustering of cardiovascular risk factors in the diabetic subpopulation, as well as uncertainties over the causal nature of known risk factors, suggest that a high-risk approach to prevention is also appropriate. Optimal allocation of resources to the two approaches requires a detailed knowledge of the disease process in individual communities.     

Reduced microvascular hyperaemia in subjects at risk of developing Type 2 (non-insulin-dependent) diabetes mellitus

Summary Abnormalities of microvascular function may be important in the pathogenesis of diabetic microangiopathy. As such changes are already present at diagnosis in patients with Type 2 (non-insulin-dependent) diabetes mellitus, subjects at risk of developing the disease, who had elevated fasting plasma glucose concentrations below the diabetic range, were studied. The maximal microvascular hyperaemic response to local heating was determined in the feet of 11 subjects with fasting hyperglycaemia and 11 age- and sex-matched control subjects. There was reduced maximal hyperaemia in the subjects with fasting hyperglycaemia (1.01 [0.71–1.57]V, median and range), when compared to control subjects (1.41 [1.32–2.13]V, p <0.001). It is unlikely that this limited vasodilation is a result of the mild degree of hyperglycaemia observed in the subjects included in this study. Further studies are therefore required to address the possible mechanisms of limited microvascular reactivity in subjects at risk of developing Type 2 diabetes. [Diabetologia (1994) 37: 214–216] Received: 26 July 1993 and in revised form: 30 August 1993     

Habitual physical activity,aerobic capacity and metabolic control in patients with newly-diagnosed Type 2 (non-insulin-dependent) diabetes mellitus: effect of 1-year diet and exercise intervention

Summary The aim of this study was to assess the effects of a 1-year intensified diet and exercise education regimen on habitual physical activity and aerobic capacity in middle-aged, obese patients with newly-diagnosed Type 2 (non-insulin-dependent) diabetes niellitus. In addition, we analysed whether the level and the changes in physical activity and aerobic capacity are related to the metabolic control of diabetes. After a 3-month basic education programme, 78 patients (45 men, 33 women) were randomly placed in an intervention or conventionally treated group. The intervention group received intensified diet education and continuous encouragement to increase physical activity which was monitored using exercise records and questionnaires. Aerobic capacity was assessed by measuring oxygen uptake at anaerobic threshold and at peak exercise. The proportion of patients with regular recreational exercise increased from 24% to 38% in the intervention men (0.10<p<0.20), remained at 54% in the conventionally treated men, increased from 53% to 70% in the intervention women (0.10<p<0.20) and from 31% to 50% (0.10<p<0.20) in the conventionally treated women. No measurable improvement was found in oxygen uptake in any of the groups. When the groups were combined, HbA_lc showed an inverse correlation with oxygen uptake at anaerobic threshold (r=–0.27, p<0.01) and maximum oxygen uptake (r =–0.28, p<0.01) at 12 months. The change in maximum oxygen uptake was linearly correlated with the change in HDL-cholesterol (r=0.28, p<0.01) and those patients with improved aerobic capacity (n=37) had higher HDL-cholesterol level at the end of the study than those (n=41) with unaltered or decreased aerobic capacity (1.27±0.27 vs 1.12±0.25 mmol·l^–1, mean±SD; p< 0.05). In conclusion, in this long-term prospective study repeated encouragement and follow-up using exercise records was not sufficient to induce a significant increase in physical activity and an improvement in aerobic capacity in diabetic patients. Our results suggest, however, that high aerobic capacity is beneficial for glycaemic control, and on the other hand, even slight increase in aerobic capacity is associated with an increase in HDL-cholesterol level.     

Five-year follow-up of islet cell antibodies in Type 2 (non-insulin-dependent) diabetes mellitus

Summary The aim was to study the frequency and appearance of cytoplasmic islet cell antibodies in relation to impairment of insulin secretory capacity and some clinical characteristics in a representative group of middle-aged (45–64 years) patients with Type 2 (non-insulin-dependent) diabetes mellitus (70 male, 63 female) at the time of diagnosis and at five-year follow-up. Non-diabetic control subjects (62 male, 82 female) were similarly examined at five-year intervals. At the baseline five out of 133 (3.8%) diabetic patients were positive for conventional and four (3.0%) for complement-fixing islet cell antibodies. Ten patients had become positive by the second screening for conventional antibodies and six for complement-fixing antibodies, but none showed negative conversion. Two non-diabetic subjects (1.5%) became antibody positive during the follow-up. Insulin treatment was started during the follow-up for four out of 15 (27%) conventional antibody positive and for one out of 121 (0.8%) antibody negative diabetic patients (p=0.001). The sensitivity of the positive conventional and complement-fixing antibody for identifying patients who developed an impairment of insulin secretory capacity (post-glucagon C-peptide 0.60nmol/l at 5-year) was 75%. The respective specificity was 90% and the positive predictive values were highest in the case of high positivity (50%). The negative predictive value of antibody positivity was close to 100%. In conclusion, islet cell antibody positivity in patients classified as Type 2 was persistent during the follow-up and predicted the future development of insulin deficiency especially in those patients with high or increasing antibody titres.     

HLA-associated susceptibility to Type 2 (non-insulin-dependent) diabetes mellitus: the Wadena City Health Study

Summary Epidemiologic data suggest that a parental history of Type 2 (non-insulin-dependent) diabetes mellitus increases the risk of 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 and Type 2 diabetes. We have previously reported evidence that HLA-DR4-linked factors may represent a homogeneous subset of diabetes susceptibility. First, HLA-DR4 frequency was higher in Type 1 diabetic study subjects with a Type 2 diabetic parent than in Type 1 diabetic subjects whose parents were not diabetic. Second, a DR4-haplotype was transmitted from the Type 2 diabetic parent to the Type 1 offspring more often than expected. These data are consistent with the hypothesis that families with a Type 2 diabetic parent and Type 1 diabetic child, heavily determined by HLA-DR4 linked factors, may represent a homogeneous subset of diabetes susceptibility. In this report, we further explore the relationship between the high-risk HLA antigen (HLA-DR4) in study subjects with differing glycaemic status (National Diabetes Data Group criteria). In this community-based study, we find evidence that HLA-DR4 is increased in study subjects with Type 2 diabetes and may be a marker for Type 2 diabetes susceptibility.     

Treatment of type 2 (non-insulin-dependent) diabetic patients with diet alone

Summary The effects of 3 months' diet therapy on glucose tolerance, plasma insulin response to oral glucose, fasting lipid levels and body weight were measured in 182 Type 2 (non-insulin-dependent) diabetic outpatients with fasting hyperglycaemia before treatment. Overall, there was a 25% improvement in glucose tolerance, a 58% increase in plasma insulin response during the glucose tolerance test, a 13.6% fall in fasting plasma triglyceride levels with no change in fasting cholesterol levels and a 5.1% fall in body weight. Of the 182 patients, 20% achieved normal glucose tolerance on diet alone for 3 months. These were mainly men of average age 63 years, who were 20% above their ideal body weight, and had milder glucose intolerance and higher residual insulin response to glucose before treatment than the 16% of patients who remained poorly controlled. These latter patients were mainly older women, 9% above their ideal body weight and with more marked glucose intolerance and less insulin response to glucose. These results demonstrate the practical limitations of this type of anti-diabetic therapy, particularly if normal glucose tolerance is a desired therapeutic aim.     

Impact of initial treatment on renal function in newly-diagnosed Type 2 (non-insulin-dependent) diabetes mellitus

Summary The impact of improved glycaemic control on renal function in newly-presenting Type 2 (non-insulin-dependent) diabetic patients has not been adequately researched. Consequently, glomerular filtration rate and effective renal plasma flow and urinary albumin excretion rates were determined in 76 subjects (age (mean (SD)): 54 (9.5) years; 50 male) of an original cohort of 110 newly-presenting normotensive non-proteinuric Type 2 diabetic patients following 6 months treatment with diet alone (n=42) or with oral hypoglycaemic agents (n=34). Significant reductions were observed in (presentation vs 6 months): body mass index (p<0.01); fasting plasma glucose (p<0.001); glycated haemoglobin (HbA₁) (p<0.001); systolic blood pressure (p<0.01); and diastolic blood pressure (p<0.001). Glomerular filtration rate declined from 117 (22) to 112 (21) ml·min^–1 (p<0.01), with unchanged effective renal plasma flow (534 (123) vs 523 (113) ml·min^–1) and filtration fraction (22.4 (3.0) vs 21.8 (3.4)%). Albumin excretion rate (median (range)) declined from 1.1 (0.1–34.7) to 0.5 (0.1–29.9) g·min^–1 (p<0.01). Changes in glomerular filtration rate ( values) were inversely correlated with presentation values (p<0.001), and positive relationships were observed with effective renal plasma flow (p<0.01), and glycated haemoglobin (p<0.05). Type 2 diabetic patients with glomerular filtration rate values at presentation over 120 ml·min^–1 demonstrated significant reduction in glomerular filtration rate (n=31; p<0.001), whilst those with original values less than 120 ml·min^–1 remained unchanged (n=45). Glomerular filtration rate, effective renal plasma flow and filtration fraction for the Type 2 diabetic patients remained elevated compared with age-controlled normal subjects (p<0.01-0.001). Albumin excretion rate at presentation and 6 months were positively correlated with fasting plasma glucose levels (p<0.05) but not renal haemodynamics. Thus, glomerular filtration rate and albumin excretion rate in newly-presenting Type 2 diabetic patients are influenced by metabolic control. Improved glycaemia for 6 months produces a reduction in glomerular filtration rate, mainly in the younger patients with values greater than 120 ml·min^–1 at diagnosis of diabetes. Despite these changes, renal haemodynamic parameters remain elevated compared with age-matched normal subjects.     

Type 2 (non-insulin-dependent) diabetes mellitus new genetics for old nightmares

Summary In the last five years, genetic markers for a large number of diseases have been localised using linkage analysis of DNA polymorphisms in affected families. The site of the genetic defect or defects leading to Type 2 (non-insulin-dependent) diabetes mellitus, a common illness with a major genetic component, remains unknown. This is due, at least in part, to the lack of large well-defined Type 2 diabetic pedigrees suitable for linkage analysis. There are several features of the disease which make large pedigrees difficult to find. The late age of onset of most probands means that informative older generations are often dead, while there is difficulty in detecting disease in younger generations. The diagnostic criteria for diabetes are, as yet, dependent on an arbitrary cut-off along a continuum of plasma glucose. The high prevalence of the disease may also produce problems as, in any given family, diabetogenic genes may be contributed by more than one parent. Varieties of the disease with a well-defined inheritance, such as maturity onset diabetes of youth, are more suitable for linkage analysis but might be due to defects at a different gene locus. Despite these difficulties, once large well-defined pedigrees have been found, linkage analysis using both candidate genes and random highly polymorphic markers is the strategy most likely to find genetic markers for the disease.     

Twenty-four-hour energy expenditure in Pima Indians with Type 2 (non-insulin-dependent) diabetes mellitus

Summary To assess the impact of Type 2 (non-insulin-dependent) diabetes mellitus on energy metabolism, 24-h energy expenditure, basal metabolic rate and sleeping metabolic rate were measured in a respiratory chamber in 151 Pima Indians, 102 with normal glucose tolerance (67 male/35 female, (mean ± SD) 28±7 years, 99±24 kg, 32±9% body fat) and in 49 with Type 2 diabetes (22 male/27 female, 35±11 years, 107±33 kg, 39±7% body fat), after at least 3 days on a weight maintaining diet. After adjustment for differences in fat-free mass, fat mass, age and sex, 24-h energy expenditure, basal metabolic rate and sleeping metabolic rate were significantly higher in diabetic patients than in control subjects (72 kcal/day, p<0.05; 99 kcal/day, p<0.005; 99 kcal/day, p<0.001 respectively). Spontaneous physical activity was similar in both groups whereas the thermic effect of food, calculated as the mean energy expenditure corrected for activity throughout the day above sleeping metabolic rate and expressed as a percentage of energy intake, was significantly lower in Type 2 diabetic patients (17.1±7.1 vs 19.8±5.6%, p<0.05). Adjusted values of 24-h energy expenditure, basal metabolic rate and sleeping metabolic rate were correlated with hepatic endogenous glucose production (r=0.22, p<0.05; r=0.22, p<0.05; r=0.31, p<0.01 respectively). Therefore, increased basal and sleeping metabolic rates, resulting in increased 24-h sedentary energy expenditure may play a role in the weight loss so often observed in Type 2 diabetic subjects in addition to the energy loss from glycosuria.     

Islet amyloid polypeptide plasma concentrations in individuals at increased risk of developing Type 2 (non-insulin-dependent) diabetes mellitus

Summary To study whether abnormal secretion of islet amyloid polypeptide is involved in the development of insulin resistance and impaired insulin secretion in Type 2 (noninsulin-dependent) diabetes mellitus, we measured islet amyloid polypeptide concentrations in 56 first-degree relatives of Type 2 diabetic subjects and in 10 healthy control subjects. Fasting islet amyloid polypeptide concentrations were similar in control subjects, glucose-tolerant and glucose-intolerant relatives (8±1, 9±1 and 11±2 fmol/ml; p=NS). The area under the islet amyloid polypeptide curve measured during an oral glucose load was larger in glucose-intolerant relatives (115±13 fmol/ml) compared to glucose tolerant relatives and control subjects (88±3 and 79±12 fmol/ml; p<0.05). The insulin response during the oral glucose load was inversely correlated with the rate of glucose disposal measured during a euglycaemic hyperinsulinaemic clamp (r=–0.725; p<0.01), while no significant correlation was observed between the corresponding values for islet amyloid polypeptide and glucose disposal (r=–0.380; p=NS). Hypersecretion of islet amyloid polypeptide is observed in glucose-intolerant first-degree relatives of patients with Type 2 diabetes. Since these patients are characterized by insulin resistance and abnormal first-phase insulin secretion, the putative role of islet amyloid polypeptide in the development of these abnormalities remains to be established. It is however, unlikely that islet amyloid polypeptide is involved in the development of insulin resistance as insulin-resistant relatives with normal glucose-tolerance showed normal islet amyloid polypeptide concentrations.     

Albuminuria in Type 2 (non-insulin-dependent) diabetes mellitus and impaired glucose tolerance in Pima Indians

Summary The prevalence of abnormal urinary albumin excretion, defined by a urine albumin to creatinine ratio>-30 mg/g (approximately equivalent to an albumin excretion rate of >-30 mg/24 h), was determined in 2728 Pima Indians aged >-15 years from the Gila River Indian Community in Arizona, a population with a high prevalence of Type 2 (non-insulin-dependent) diabetes mellitus. Excessive albumin excretion was present in 8% of subjects with normal glucose tolerance, 15% of those with impaired glucose tolerance, and 47% of subjects with diabetes. The intermediate prevalence of abnormal albuminuria in those with impaired glucose tolerance suggests that hyperglycaemia even at levels below those diagnostic of diabetes is associated with renal abnormalities in some subjects and that these abnormalities may precede the onset of diabetes. Abnormal albuminuria at levels not reliably detected by the usual dipstick methods was commonly observed in Pima Indians with diabetes, even those with diabetes of recent onset. Associations were found with age, duration of diabetes, level of glycaemia, blood pressure, and treatment with insulin.     

Hyperinsulinaemia in youth is a predictor of Type 2 (non-insulin-dependent) diabetes mellitus

Summary This study aimed to compare plasma insulin concentrations across the age-range from childhood to old age in the populations of Nauru and Tuvalu, and to assess their relationship to the incidence of impaired glucose tolerance and diabetes in young Nauruans. The studies, performed in 1975 and 1976, found that Nauru had a higher prevalence of Type 2 (non-insulin-dependent) diabetes mellitus than Tuvalu. Both studies included subjects of 8–29 years of age (n=320 in Nauru, n=318 in Tuvalu) and on these subjects glucose tolerance status, body mass index and fasting and 2-h (post 75 g glucose load) plasma insulin concentrations were determined. In Nauru, follow-up surveys in 1982 and 1987 included many of the subjects first seen in 1975/1976, allowing the incidence and natural history of glucose intolerance to be studied. Within the group of subjects with normal glucose tolerance, there was no effect of age on plasma insulin distributions in either population. However, in both populations, 8–19 year old subjects with normal glucose tolerance had higher body mass index-adjusted geometric mean fasting and 2-h insulin concentrations than older age-groups (p < 0.001 for fasting insulin). Body mass index-adjusted geometric mean 2-h plasma insulin was higher in subjects with abnormal glucose tolerance relative to those with normal glucose tolerance in both populations. In Nauruans, 2-h insulin levels at baseline were predictive of impaired glucose tolerance and Type 2 diabetes in 1982, and fasting and 2-h insulin levels predicted development of Type 2 diabetes in 1987. Hyperinsulinaemia in the presence of normal glucose tolerance is evident in young people in Nauru and Tuvalu, as has been demonstrated in other populations known to have high susceptibility to Type 2 diabetes. Even in youth, elevated fasting and 2-h insulin concentration is predictive of subsequent deterioration in glucose tolerance.     

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.     

Modulation of hepatic glucose production by non-esterified fatty acids in Type 2 (non-insulin-dependent) diabetes mellitus

Summary To study the effect of changes in plasma non-esterified fatty acid concentration on suppression of hepatic glucose production by insulin eight Type 2 (non-insulin-dependent) diabetic patients participated in three euglycaemic, hyperinsulinaemic (108pmol · m^2–1 · min^–1) clamp studies combined with indirect calorimetry and infusion of [3-³H]-glucose and [1-¹⁴C]palmitate; (1) a control experiment with infusion of NaCl 154 mmol/l, (2) heparin was infused together with insulin, and (3) an antilipolytic agent, Acipimox, was administered at the beginning of the experiment. Six healthy volunteers participated in the control experiment. Plasma non-esterified fatty acid concentrations during the insulin clamp were in diabetic patients: (1) 151±36 mol/1, (2) 949±178 mol/l, and (3) 65±9 mol/l; in healthy control subjects 93±13 mol/l. Non-esterified fatty acid transport rate, oxidation and non-oxidative metabolism were significantly higher during the heparin than during the Acipimox experiment (p<0.001). Suppression of hepatic glucose production by insulin was impaired in the diabetic compared to control subjects (255±42 vs 51±29 mol/min, p<0.01). Infusion of heparin did not affect the suppression of hepatic glucose production by insulin (231±49 mol/min), whereas Acipimox significantly enhanced the suppression (21±53 mol/min, p<0.001 vs 154 mmol/l NaCl experiment). We conclude that insulin-mediated suppression of hepatic glucose production is not affected by increased non-esterified fatty acid availability. In contrast, decreased non-esterified fatty acid availability enhances the suppression of hepatic glucose production by insulin.     

Analysis of the HepG2/erythrocyte glucose transporter locus in a family with Type 2 (non-insulin-dependent) diabetes and obesity

Summary A recent report has shown an association between a specific Xba1 restriction fragment of the human HepG2-Erythrocyte glucose transporter gene and Type 2 (non-insulin dependent) diabetes. To further examine the significance of this finding we have studied Type 2 diabetic pedigrees for linkage between the Xba1 alleles of this glucose transporter gene and diabetes. One large pedigree, in which the diabetic phenotype was associated with obesity and insulin resistance, was informative. In this family the disease did not co-segregate with the glucose transporter locus. Formal linkage analysis was performed assuming autosomal dominant inheritance with age-dependent penetrance. At putative gene frequencies of 0.01 and 0.001 the logarithin of the odds for linkage versus non-linkage at a recombination fraction of 0.001 was –1.84 and –3.32 respectively (a value of <-2 indicates definite non-linkage). Genetic variations in the HepG2-Erythrocyte glucose transporter gene are unlikely to be responsible for the development of diabetes in this pedigree.     

Effect of protein intake on glycaemic control and renal function in Type 2 (non-insulin-dependent) diabetes mellitus

Summary Recent clinical investigations have suggested that dietary protein intake may modulate the progression of diabetic nephropathy and influence glycaemic control in Type 2 (non-insulin-dependent) diabetes mellitus. Twelve normotensive Type 2 diabetic patients with microalbuminuria took part in a randomized cross-over trial of a 3-week high protein diet (2.0 g/kg desirable weight per day) and a 3-week moderate protein diet (0.8 g/kg desirable weight per day) to test the simultaneous effect of protein intake modulation on glycaemic control and renal function. Both diets were isoenergetic and the moderate protein diet was supplemented with calcium and phosphate. Renal function and glycaemic control were evaluated at the beginning and at the end of each diet. The moderate protein diet reduced the urinary albumin excretion rate, glomerular filtration rate, creatinine clearance, and proteinuria without adversely affecting glycaemic control; fasting glycaemia and the ratio of fructosamine to proteins were significantly reduced. The high protein diet induced similar improvements in glycaemic control but small changes in renal function.     

Factors associated with basal metabolic rate in patients with Type 2 (non-insulin-dependent) diabetes mellitus

Summary To examine determinants of basal metabolic rate we studied 66 Type 2 (non-insulin-dependent) diabetic and 24 healthy age- and weight-matched control subjects with indirect calorimetry and infusion of [³H-3-] glucose. Eight Type 2 diabetic patients were re-studied after a period of insulin therapy. Basal metabolic rate was higher in Type 2 diabetic patients than in control subjects (102.8 ± 1.9 J · kg LBM^–1-min^–1 vs 90.7 ± 2.8 J · kg LBM^–1;min^–1; p<0.01) and decreased significantly with insulin therapy (p <0.01). The basal rate of hepatic glucose production was higher in Type 2 diabetic patients than in control subjects (1044.0 ± 29.9 vs 789.3 ± 41.7 mol/min; p <0.001) and decreased after insulin therapy (p <0.01). Hepatic glucose production correlated positively with basal metabolic rate both in Type 2 diabetic patients (r = 0.49; p <0.001) and in control subjects (r = 0.50; p<0.05). Lipid oxidation was increased in Type 2 diabetic patients compared with control subjects (1.68 ± 0.05 vs 1.37 ± 0.08 mol · kg LBM^–1 · min^–1'; p <0.01) and decreased significantly after insulin therapy (p <0.05). The rate of lipid oxidation correlated positively with basal metabolic rate both in Type 2 diabetic patients (r = 0.36; p <0.01) and in control subjects (r = 0.51; p <0.01). These data demonstrate that basal metabolic rate, rates of hepatic glucose production and lipid oxidation are interrelated in Type 2 diabetic patients. A reduction of the hepatic glucose production, however, is associated with a reduction in lipid oxidation, which in turn, may result in a reduction in basal metabolic rate.     

Type 2 (non-insulin-dependent) diabetes mellitus,migration and westernisation: The Tokelau Island Migrant study

Summary The migration of Tokelauans from a traditional atoll in the Pacific to urban New Zealand is associated with an increased prevalence and incidence of Type 2 (non-insulin-dependent) diabetes mellitus over the period 1968–1982. During the same period, a lesser but definite increase is seen among non-migrants in Tokelau. The age standardised prevalence rates rose from 7.5 and 11.7 to 10.8 and 19.9 per 100 respectively in the male and female migrants compared with an increase from 3.0 and 8.7 to 7.0 and 14.3 per 100 in the nonmigrant males and females respectively. The incidence of diabetes is shown to be consistently higher in the migrants compared to the non-migrants giving relative risks of 1.5 in males and 1.9 in females. The factors most likely contributing to this difference, are changes to a higher calorie, high protein diet, higher alcohol consumption, a greater weight gain and altered levels of physical activity in the migrants. A number of populations in the Pacific have been shown to have a low rate of diabetes in their traditional setting, but may have a genetic predisposition for diabetes which responds to factors in the urban industrialised environment and life-style. The social and economic changes taking place in Tokelau are also clearly increasing the risk of diabetes. To reverse these trends and prevent the development of complications of Type 2 diabetes, it will be important to institute preventive programmes and to follow up the population in both environments for long-term outcomes, including mortality.     

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.