Five-Year Follow-Up Study onPlasma Insulin Levels in NewlyDiagnosed N1DDM Patientsand Nondiabetic Subjects

Leo K. Niskanen, MDMatti I. Uusitupa, MDHelena Sarlund, MDOnni Siitonen, MDKalevi Pyorala, MD

A representative group of middle-aged (45- to 64-yr-old)patients with non-insulin-dependent diabetes mellitus(NIDDM) (n = 133; 70 men, 63 women) were examinedat the time of diagnosis and 5 yr afterward for metaboliccontrol and insulin response to oral glucose; 144nondiabetic control subjects (62 men, 82 women) weresimilarly examined twice between 5-yr intervals. At the5-yr examination, 56 of the diabetic patients (36 men, 20women) were on diet therapy only, 60 (27 men, 33women) received oral antidiabetic drugs, and 5 weretreated with insulin. The metabolic control of diabeticpatients was poor at the time of diagnosis and 5-yrexamination. Fasting plasma insulin levels were higherin diabetic patients than in control subjects both atbaseline (23 ± 2 vs. 14 ± 1 mU/L, P < 0.01, for men;26 ± 2 vs. 15 ± 1 mU/L, NS, for women) and 5-yrexamination (19 ± 1 vs. 16 ± 2 mU/L, NS, for men;29 ± 5 vs. 15 ± 1 mU/L, P < 0.05, for women). Thefrequency of insulin deficiency in diabetic patientsbased on a postglucagon (1 mg i.v.) C-peptide level<0.60 nM was 3.3% at the 5-yr examination, indicatingthat true insulin deficiency was uncommon during thefirst years after diagnosis of diabetes in middle-agedsubjects. Diabetes Care 13:41-48, 1990

Most non-insulin-dependent diabetes mellitus(NIDDM) patients are poorly controlled bydiet and oral hypoglycemic agents (1,2). It iscommonly believed but not confirmed that

progressive deterioration of endogenous insulin secre-tion capacity often occurs in NIDDM. The term sec-ondary drug failure refers to diabetic patients who losetheir initial responsiveness to oral hypoglycemic drugs,particularly sulfonylureas (1,2). The criterion for sec-ondary drug failure in most studies has been persistent

hyperglycemia despite oral hypoglycemic drug therapy(2), but hyperglycemia is not a reliable indicator of in-sulin deficiency. There is a subgroup of patients withNIDDM who will become insulin dependent with time,but the frequency of this subtype of diabetes has re-mained unknown due to the lack of prospective studieson insulin secretion capacity in diabetic patients whohave not initially required insulin treatment (3). In thisstudy, fasting and postglucose plasma insulin levels wereexamined at the time of diagnosis and 5 yr afterward ina representative group of NIDDM patients and nondi-abetic control subjects. The frequency of insulin defi-ciency in diabetic patients was also examined at the 5-yr examination by determining plasma C-peptide levelsin connection with an oral glucose tolerance test andafter a glucagon stimulation test.

RESEARCH DESIGN AND METHODS

The original study population consisted of 133 patientswith newly diagnosed NIDDM aged 45-64 yr and 144randomly selected nondiabetic control subjects of thesame age group. The collection of both groups was con-ducted from 1 May 1979 to 31 December 1981 from adefined area in the county of Kuopio in eastern Finland.This area included 18 rural communities and 1 urban

C-peptideGlucose

1 nM = 3.02 ng/ml1 mM = 18 mg/dl

Insulin 1 pM = 0.167 (lU/ml

From the Departments of Medicine and Clinical Nutrition, University of Kuopio,Kuopio, Finland.

Address correspondence and reprint requests to Leo Niskanen, MD, Depart-ment of Medicine, University of Kuopio, 70210 Kuopio, Finland.

Received for publication 21 March 1989 and accepted in revised form 2August 1989.

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community (Kuopio). The number of residents in thissurvey area was 180,831 at the end of 1980.

Diabetic patients (70 men, 63 women) were referredto the study by general practitioners working in com-munity health centers in the survey area. The diagnosisof diabetes was primarily made in the clinical settingand was confirmed with an oral glucose tolerance testthat used the diagnostic criteria recommended by theWorld Health Organization's Expert Committee on Di-abetes Mellitus (4,5). Subjects with secondary diabetes,thyroid diseases, alcoholism, renal insufficiency, overtcarcinoma, or subjects in institutional care settings werenot eligible for the study. All diabetic patients were non-ketotic at the time of diagnosis, and none needed insulintreatment during the follow-up period of at least 3 mo.The nondiabetic control population (62 men, 82 women)was selected randomly from the population registers ofthe study area by random number tables. The formation,representativeness of the study population, and methodsof the baseline examination have been described pre-viously in detail (4). The 5-yr follow-up examination ofnewly diagnosed diabetic patients and nondiabetic con-trol subjects was conducted between August 1985 andJanuary 1986.

Eighty diabetic patients participated in the diet inter-vention study that lasted 1 yr (6). Otherwise, they werereferred to the primary-care practitioners after baselineexamination. Formation of the 5-yr study population isshown in Table 1. Data are given on subjects who par-ticipated in the baseline and 5-yr examination. Exami-nations of the 5-yr study were conducted, when appro-priate, according to the same methods and by the sametrained nurses as in the baseline study.Medical history. Medical history included a history ofcardiovascular, renal, and other significant chronic dis-ease and the use of the following drugs: digitalis, di-

uretics, nitroglycerin, fi-blockers, other hypertensiveagents, hormone substitutes, and drugs for treatment ofdiabetes and physical activity. The place where themanagement of diabetes occurred and the frequency ofvisits to the doctor and diabetic nurse were also regis-tered. Medical history was ascertained by reviewing thepatient records of all subjects. Fasting blood glucose,body weight, and the two latest blood glucose valueswere collected 1 yr after diagnosis. The duration of dif-ferent modes of treatment for diabetes (diet, oral hypo-glycemic agents, and insulin) was ascertained from themedical records.Anthropometric measurements. Standing height wasmeasured without shoes in an erect position and readon the scale to the nearest 1.0 cm. Body weight wasmeasured with an electrical weighing machine (Seca,FRG) with subjects barefoot and dressed in lightweightshorts. Weight was read on the scale to the nearest 1kg. Body mass index (BMI) was calculated from the for-mula body weight (kg)/height (m2). Subscapular skin foldwas measured beneath the apex of the scapula with theHarpendercaliper (British Indicators, St. Albans, UK) bythe same nurse at both examinations. Measurements wereperformed twice, and the mean value of the two read-ings was used.Biochemical methods. An oral glucose tolerance testwas performed with a glucose dose of 75 g. Blood sam-ples for glucose, C-peptide, and insulin determinationswere drawn before the glucose load and 1 and 2 h af-ter it.

At the 5-yr examination, glucose was determined bya glucose dehydrogenase method (Merck, Darmstadt,FRG) from plasma samples frozen to -70°C until thedetermination. Glucose samples were analyzed at the5-yr study with the Multi-Stat Micro Centrifugal Ana-lyzer (Instrumentation, Lexington, MA). At the baseline

TABLE 1Study population and anthropometric characteristics

Original study population (n)Age (yr)Body mass index (kg/m2)Subscapular skin-fold thickness (mm)Died during follow-upRefused to participate in follow-up studyIncomplete examination

Five-year study population (n)Age (yr)Body mass index (kg/m2)Subscapular skin-fold thickness (mm)

Men

Diabetic

7054.7 ± 0.7*+29.3 ± 0.6

26 ± 1§513

6159.1 ± 0.728.4 ± 0.5||

23 ± 1*§

Control

6252.9 ± 0.726.5 ± 0.4

19 ± 1111

5958.0 ± 0.726.4 ± 0.4

17 ± 1*

Women

Diabetic

6357.1 ± 0.7*§31.3 ± 0.7

31 ± 1§330

5762.3 ± 0.7tt28.8 ±0.711

27 ± 2*||

Control

8254.3 ± 0.627.1 ± 0.6

25 ± 1140

7759.1 ± 0.627.2 ± 0.6

24 ± 1

Results are means ± SE.*P < 0.05; analysis of covariance with group (diabetic vs. control) as factor.+P < 0.05, §P < 0.01, ||P < 0.001; analysis of covariance with group (diabetic vs. control) as factor and age as cofactor used in comparisonof groups.tP < 0.01, HP < 0.001, compared with respective value at baseline study (paired t test).

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L.K. NISKANEN AND ASSOCIATES

study, determinations were conducted from whole bloodby a glucose oxidase method (Glox, Kabi AB, Stock-holm). The method used at the 5-yr study was comparedwith that used at the baseline study; Multi-Stat gave neg-ligibly higher values (r = 0.989, y = 1.107x + 0.38).To compare plasma glucose values with blood glucoselevels at the baseline study, blood glucose levels weremultiplied by 1.12 (5).

Samples for plasma insulin were drawn into chilledtubes. After separation of plasma, samples were frozenimmediately at -70°C until the determination. At the5-yr examination, plasma insulin was determined by acommercial double-antibody solid-phase radioimmu-noassay (Phasedeph, Pharmacia, Uppsala, Sweden). Thedetection limit of the assay was 2.5 mU/L, and coeffi-cient of variation was <5%. At the baseline examina-tion, serum insulin was also determined by radioim-munoassay but with different antiserum (M8309, Novo,Copenhagen). This method was compared with that usedat the 5-yr examination; the Phasedeph antiserum gave~7% higher values than the Novo antiserum (r = 0.952,y = 0.930x + 2.55).

Plasma C-peptide was determined by radioimmu-noassay (antiserum M1230, Novo) in connection withan oral glucose tolerance test at the 5-yr study. C-pep-tide response to 1 mg glucagon i.v. was determinedaccording to Faber and Binder (7) in patients treatedwith insulin and in diabetic patients treated with diet ororal hypoglycemic drugs whose maximal C-peptide re-sponse to an oral glucose tolerance test remained <1.00nM. Glycosylated hemoglobin (HbA,) was determinedby column chromatography (Quick-Step Fast Hemoglo-bin Test System, Isolab, Akron, OH) after incubation in0.9% saline solution for 12 h.Statistical methods. All values are given as means ±SE. Calculations concerning insulin were conducted onlog-transformed data, but unlogged data are shown forillustrative purposes. The differences between the groupswere assessed by analysis of covariance (ANCOVA), x2-test with Yate's correction, or unpaired t test. Time-re-lated changes within the group were analyzed by pairedt test.

The study was approved by the ethical committee ofKuopio University Central Hospital.

RESULTS

CLINICAL 5-YR FOLLOW-UP DATABody weight, subscapular skin folds, and physicalactivity. At baseline examination, mean BMI was higherin diabetic men than control men (Table 1). At the 5-yrexamination, BMI was higher in diabetic men than incontrol men. Diabetic women were also more obese atbaseline examination, but at the 5-yr examination, nosignificant difference was found between diabetic andcontrol women. Sixty-four percent of diabetic men wereobese at baseline examination (criterion for obesityBMI >27 kg/m2). At the 5-yr examination, 56% of di-

abetic men were still obese. Among female diabetic pa-tients, 91 % were obese at baseline (criterion for obesityBMI >25 kg/m2); at the 5-yr examination 79% wereobese.

At baseline examination, diabetic patients had thickersubscapular skin folds than control subjects (P < 0.01-0.001). Although the skin folds were decreased in thick-ness in diabetic patients at the 5-yr examination com-pared with the baseline examination, they were stillthicker than those of control subjects (P < 0.01-0.001).

Regular leisure-time physical activity for at least 30min at least 3 times/wk was performed by 4 (6.3%)diabetic and 5 (8.5%) control men at the baseline studyand by 1 (1.8%) diabetic and 1 (1.3%) control women.However, at the 5-yr examination, ~50% of the studypopulation reported regular physical leisure-time activ-ity; 33 (52.3%) diabetic and 38 (64.4%) control menand 27 (47.4%) diabetic and 37 (48.1%) control women.Many subjects in the study population had retired bythe follow-up period, which may explain the great in-crease in leisure-time physical activity.Incidence of diabetes and impaired glucose toler-ance in control subjects. At baseline examination, theprevalence of impaired glucose tolerance according toWorld Health Organization criteria (5) was 24% in non-diabetic men and 27% in nondiabetic women. Thesefigures remained about the same at the 5-yr examination(22% for men, 30% for women). The clinical diagnosisof NIDDM had been made in two control subjects dur-ing the 5-yr follow-up (1 man, 1 woman). Both hadimpaired glucose tolerance at baseline examination. Inaddition, 11 control subjects (6 men, 5 women) provedto have diabetes at the 5-yr examination according toan oral glucose tolerance test. Diagnosis was based onelevated 2-h plasma glucose levels. The 13 new diabeticsubjects were excluded from the analyses concerninganthropometric characteristics, plasma glucose, insulin,and C-peptide levels between diabetic and nondiabeticcontrol subjects. Altogether, 20% (3 men, 4 women) ofcontrol subjects with impaired glucose tolerance atbaseline developed diabetes, whereas the respective fig-ure was 5.3% (4 men, 2 women) in subjects with normalglucose tolerance at baseline examination (P < 0.05).Cardiovascular drug treatment. The frequency of theuse of cardiovascular drugs (e.g., digitalis, diuretics, andfj-blocking agents) is shown in Table 2. The use of thesedrugs was 2-3 times more common in diabetic subjectsthan in control subjects of either sex.Mode of treatment and metabolic control of diabe-tes. Most diabetic patients (79%) were treated at localhealth centers during the last year before the 5-yr ex-amination. The mean frequency of visits to the doctorwas twice per year. Altogether, 17% of the diabetic pa-tients had not seen a doctor during the last year beforethe follow-up study.

At baseline, all diabetic patients were on diet only,and none required insulin at least during the first 3 moafter diagnosis. At the 5-yr examination, 56% of maleand 35% of female diabetic patients were treated with

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TABLE 2Frequency of use of cardiovascular drugs at baseline and5-yr examination by sex

Variable

MennDigitalisDiureticsB-Blocking

agentsWomen

nDigitalisDiureticsB-Blocking

agents

Diabetic

Baseline

6415(23)20(31)

26(41)

5725 (44)29(51)

19(33)

5-yrexamination

14 (22)19(30)

28 (44)

22 (39)29(51)

23 (40)

Baseline

603(5)5(8)

9(15)

776(8)

17(22)

10(13)

Control

5-yrexamination

4(7)7(12)

15(25)

12(16)18(23)

17(22)

Percentage of prevalence in parentheses.

diet only, and 42% of male and 58% of female diabeticpatients received oral hypoglycemic drugs. Most pa-tients were treated with sulfonylureas, many receivingglyburide. In addition to sulfonylurea, 13(11 %) patientsreceived metformin. Four (7%) patients were treated withmetformin only. One male (2%) and 4 female (7%) di-abetic patients received insulin treatment at the 5-yrexamination. None of the diabetic patients who died

during the follow-up or refused to participate in the fol-low-up examination received insulin treatment accord-ing to patient records.

The fasting glucose levels in diabetic patients at base-line and at the 5-yr examination by mode of treatment(diet vs. oral agents) are shown in Table 3. Diabeticpatients with oral hypoglycemic drug therapy were onaverage more hyperglycemic than those on diet therapyonly (P < 0.05; ANCOVA adjusted for age for bothsexes). Also, HbA, was higher in diabetic patients withoral hyperglycemic drug treatment (8.5 ± 0.3 vs. 9.6 ±0.3% for men, P < 0.05, and 9.1 ± 0.5 vs. 10.0 ±0.3% for women, NS). The number of diabetic patientswith insulin treatment was small, but metabolic controlwas poor on average in this group (HbA, 10.2 ± 0.9%).Blood glucose and plasma insulin responses to glu-cose load in diabetic patients and control subjects.Glucose and insulin responses determined with an oralglucose tolerance test at baseline and the 5-yr exami-nation according to mode of treatment (diet and oraldrugs) are presented in Table 3. At the 5-yr examination,diabetic patients with oral drug therapy had higher post-load glucose levels than those with diet therapy only(P < 0.05; ANCOVA for both sexes adjusted for age).There was no statistically significant difference in thefasting insulin levels between the groups, but postglu-cose insulin levels were higher in diabetic men with diettherapy than in those with oral drug treatment (P <0.05, ANCOVA), whereas in women no statistically sig-nificant difference was found between these groups. In

TABLE 3Fasting glucose and insulin levels and 1- and 2-h postload glucose and insulin levels at baseline examination and 5-yrexamination by mode of treatment in diabetic and control subjects by sex

MennFasting plasma glucose (mM)1-h plasma glucose (mM)2-h plasma glucose (mM)Fasting plasma insulin (mU/L)1-h plasma insulin (mU/L)2-h plasma insulin (mU/L)

WomennFasting plasma glucose (mM)1-h plasma glucose (mM)2-h plasma glucose (mM)Fasting plasma insulin (mU/L)1-h plasma insulin (mU/L)2-h plasma insulin (mU/L)

Baseline

6311.2 ± 0.419.1 ± 0.618.0 ± 0.8

23 ± 258 ± 557 ± 6

5312.6 ± 0.620.8 ± 0.720.8 ± 0.8

26 ± 272 ± 872 ± 8

Diabetic

5-yr examination

Diet

3610.4 ±0.617.3±0.816.3 ±0.9

20 ± 263 ± 869 ± 10

2010.9 ±0.818.1 ± 1.318.9±1.5

23 ± 659 ± 1470 ± 15

Oral drugs

2712.7 ± 0.719.5 ± 0.719.8 ± 0.8

18 ± 240 ± 546 ± 9

3313.5 ± 0.621.6 ± 0.723.4 ± 0.8

32 ± 771 ± 2564 ± 14

Baseline

535.6 ± 0.17.8 ± 0.36.2 ± 0.314 ± 181 ± 741 ± 4

715.4 ± 0.16.9 ± 0.36.6 ± 0.215 ± 180 ± 669 ± 5

Control

5-yr examination

535.5 ± 0.19.0 ± 0.3*6.6 ± 0.216 ± 2

102 ± 1067 ± 9

725.4 ± 0.18.4 ± 0.3*7.2 ± 0.2t15 ± 193 ± 992 ± 9

Results are means ± SE.*P < 0.001, iP < 0.01, compared with respective values at baseline and at 5-yr examination. Differences between groups (diabetic vs. controlor diet vs. oral drug treatment) are shown in the text.

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I.K. NISKANEN AND ASSOCIATES

100

E

50

100B

I I

0-hour 1-hour 2-hour 0-hour 1-hour 2-hourFIG. 1. Fasting, 1-, and 2-h plasma insulin level (IRI) in male (A) and female (0) diabetic and control subjects at baselineand 5-yr examination. Differences between groups (diabetic vs. control) are shown in text. • , Diabetic patients; O,control subjects; solid line, baseline; dotted line, 5-yr examination. Results are means ± SE.

control subjects, the 1-h glucose levels in both sexesand the 2-h glucose levels in women were higher (P <0.01-0.001) at the 5-yr examination than baseline ex-amination. Fasting insulin levels remained the same incontrol subjects, whereas an increase in postglucose in-sulin levels was seen during the follow-up.

Figure 1 shows plasma insulin responses to an oralglucose load in diabetic patients with diet and oral drugtherapy combined and in control subjects by sex atbaseline and the 5-yr examination. The fasting insulinlevel was higher in diabetic patients at baseline (P =0.005 for men and P = 0.093 for women) and the 5-yrexamination than in control subjects (P = 0.154 formen and P = 0.011 for women, ANCOVA adjusted forage and BMI) and remained about the same in all groups.At both examinations, diabetic patients had lower 1-hinsulin levels than control subjects (P < 0.001 for bothsexes). The 2-h insulin levels at baseline were higher indiabetic patients (P = 0.030 for men and P < 0.05 forwomen, ANCOVA), whereas at the 5-yr examination,2-h insulin levels were lower in diabetic patients thanin control subjects (P = 0.090 for men and P < 0.001for women, ANCOVA).

Diabetic subjects treated with insulin at the 5-yr ex-amination (n = 5) had on average lower insulin levelsat the baseline study (fasting insulin 12 ± 4 mU/L, 1-hinsulin 17 ± 4 mU/L, and 2-h insulin 16 ± 5 mU/L).Relationship of fasting plasma glucose level to plasmainsulin and C-peptide at 5-yr examination. Figure 2shows fasting, 1-, and 2-h plasma insulin and C-peptidelevels in diabetic patients according to different fastingplasma glucose levels at the 5-yr examination; the higherthe fasting plasma glucose levels, the lower the postglu-cose insulin and C-peptide levels.

Frequency of insulin deficiency among diabetic sub-jects at 5-yr examination. Altogether, 9 of 114 (8%)diabetic patients treated with diet or a hypoglycemicdrug had a maximal C-peptide level lower than 1.00nM according to an oral glucose tolerance test. The glu-cagon test was performed on these 9 diabetic patientsand on all who received insulin treatment (n = 5). Table4 shows the frequency of insulin deficiency in diabeticpatients assessed by the postglucagon C-peptide level.Four diabetic patients (3.3%) had C-peptide levels <0.60nM after glucagon stimulation, with 1 patient having anundetectable value. The 4 diabetic patients received in-sulin treatment. Maximal postglucagon C-peptide re-sponse remained lower than 1.00 nM in 7 (5.8%) dia-betic patients.

DISCUSSION

Main pathogenetic mechanisms leading to hy-perglycemia in NIDDM are peripheral insulinresistance, increased hepatic glucose produc-tion, and impaired insulin secretion (8-10).

There is, however, a considerable dispute concerningthe impact of impaired insulin secretion capacity on thedevelopment of unresponsiveness to drug treatment inNIDDM patients with a longer duration of disease. Mostprevious studies dealing with insulin secretion in NIDDMpatients have been cross-sectional studies conducted inpatients recruited from diabetic clinics, or subjects havebeen otherwise selected, such as Pima Indians (11-14).None of the earlier follow-up studies included nondi-abetic control subjects. In a short report on 225 newlydiagnosed diabetic patients followed for 5 yr, Lohmann

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INSULIN SECRETION AND DEFICIENCY IN NIDDM

(i/n

E_ 50

gcO)cw«J 10U-

•

1 I I

CD

O) C

c^~ 1CO

cc ni i m i ir nr

E50

3OcI 10

•

11

CD

Q. 3

( I ) | 2

I"11

-

•

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s 5 0

CVJ 10

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I II mFIG. 2. Fasting, 1-, and 2-h postglucose plasma insulin (IRI)and C-peptide levels in diabetic patients at 5-yr examina-tion according to fasting glucose levels (I, plasma glu-cose <10.0 mM [n = 21]; II, 10.1-12.0 mM [n = 21]; III,>12.1 mM [n = 74]). Results are means ± SE.*P < 0.05, **P < 0.001, ***P < 0.001, compared with groupI (analysis of covariance adjusted for sex, age, and bodymass index).

and Verlohren (15) found that fasting and stimulatedplasma insulin did not show any constant trend of de-terioration in diabetic patients treated with oral drugs ordiet only. Hadden et al. (16) followed 160 NIDDM pa-tients for 6 yr from the time of diagnosis. In subjectswith diet or oral drug treatment, fasting plasma insulinlevels also remained about the same.

In this study, plasma insulin response to an oral glu-cose load and the frequency of the real insulin defi-ciency were examined in a representative group of pa-tients who were originally classified as having NIDDMand who participated in the comparable study both atthe time of diagnosis and 5 yr afterward. The fastingplasma insulin level was higher in our diabetic patientsthan in control subjects both at the time of diagnosisand at the 5-yr examination. In previous studies, fastingplasma insulin levels have been either normal or ele-vated depending on the group of NIDDM patients stud-

ied (11-13). In accordance with Hadden et al. (16), ourdiabetic patients showed no constant decline in the fast-ing plasma insulin level during follow-up.

Another characteristic for NIDDM is delayed and ex-aggerated insulin response to glucose (11-13). Theplasma insulin responses of our patients showed a pro-longed response to glucose at both examinations. Com-pared with the baseline study, the 1- and 2-h serumplasma insulin levels were lower at the 5-yr examinationin diabetic patients, whereas the nondiabetic controlsubjects showed an increase. Interpretation of these time-related changes was hampered by the different methodsused for determination of plasma insulin, but lowerplasma insulin responses in diabetic patients at the 5-yrexamination might indicate a slowly deteriorating in-sulin secretion capacity in NIDDM. On the other hand,hyperglycemia may also diminish insulin secretion ca-pacity (17). In accordance with this, there was an in-verse relationship between postglucose plasma insulinor C-peptide levels and blood glucose at the 5-yr ex-amination. The fasting glucose levels in diabetic patientswere about the same at time of diagnosis and the 5-yrexamination; therefore, the change in the degree of hy-perglycemia did not appear to be a confounding factorin the interpretation of the results on insulin responses.

Pancreatic (3-cell function has been estimated in aprospective study (16) with the so-called homeostasismodel assessment based on the measurements of fastingblood glucose and plasma insulin levels only (18). It wasestimated that a decreasing (3-cell function of 1.5%/yroccurs in NIDDM patients. Differences in insulin clear-ance and its hepatic extraction might also explain thedeclining trend in diabetic patients during the follow-up. The simultaneous measurement of plasma insulinand C-peptide levels at both examinations would haveclarified this issue (19), but C-peptide levels were notmeasured in this study at the baseline examination.

Oral hypoglycemic drugs, mainly sulfonylureas, werereceived by —50% of the diabetic patients at the 5-yrexamination. These drugs increased plasma insulin lev-els for at least a short-term basis, but with longer du-ration of treatment, extrapancreatic actions were con-sidered more important (20). In this study, no consistentdifferences were found in plasma insulin levels betweendiet- and drug-treated groups.

The proinsulin-insulin ratio may be increased inNIDDM patients compared with control subjects, which

TABLE 4Frequency of insulin deficiency in diabetic patients (n =121) assessed by postglucagon C-peptide level at 5-yr ex-amination

Maximal C-peptide level (nM) n

<0.017<0.60<1.00

1 (D4 (3.3)7 (5.8)

Percentages are in parentheses.

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L.K. NISKANEN AND ASSOCIATES

might influence the results on insulin levels because ofthe cross-reactivity of proinsulin with insulin determi-nation (21,22).

The nondiabetic control subjects of this study showedworsening of glucose tolerance and an increase in post-glucose plasma insulin levels, even after exclusion ofsubjects who had diabetic values at the 5-yr examina-tion. These changes probably represent increasing in-sulin resistance associated with aging (23).

We evaluated endogenous insulin secretion capacityat the 5-yr examination by measuring serum C-peptideafter intravenous glucagon in all diabetic patients withinsulin treatment and in patients whose maximal C-pep-tide response to an oral glucose tolerance test remained<1.00 nM. Postglucagon C-peptide has been shown tobe an appropriate and repeatable method for measuringendogenous insulin secretion capacity (24,25). It hasbeen shown that diabetic patients with postglucagon C-peptide levels <0.60 and <1.00 nM frequently andsometimes, respectively, require insulin treatment (26-28). In this study, the frequency of insulin deficiencywith the cutoff point of 0.60 nM for postglucagon C-peptide at the 5-yr examination was only 3.3%, andwith the cutoff point of 1.00 nM the figure was 5.8%.There were no other prospective studies on the fre-quency of true insulin deficiency conducted by follow-ing the patients with newly diagnosed NIDDM. In pre-vious studies (2), the criterion for secondary failure oforal hypoglycemic agents has been persistent hypergly-cemia of a variable degree, which is not a reliable in-dicator of insulin dependency.

Laakso et al. (29) studied the frequency of insulin de-pendency in 171 insulin-treated originally NIDDM pa-tients with a mean duration of disease of 12.6 yr. Thisstudy showed that the frequency of insulin dependencywith the cutoff point of 0.60 nM for postglucagon C-peptide was 3.1 %, which was the same frequency as inour follow-up examination. Higher prevalences of in-sulin dependency in patients with the onset of diabetesafter the age of 30 yr have been reported from the Islandof Falster, Denmark (30), where 55% of insulin-treateddiabetic patients showed fasting C-peptide levels <0.40nM, indicating insulin dependency. Similar results havebeen reported by Welborn et al. (31) in a study con-ducted in a hospital clinic and country survey of diabeticpatients. However, in these studies the age of onset ofdiabetes was lower and the proportion of normal-weightsubjects substantially higher than in our patients, andonly fasting C-peptide was measured.

When our baseline examination was performed, it be-came evident that all newly diagnosed NIDDM patientsfrom the area could not be recruited into the study.However, because all newly diagnosed patients aged45-64 yr requiring insulin therapy were principally re-ferred to our hospital from the local health centers andprivate practitioners, there was reason to believe thatthe number of patients requiring insulin treatment wasnot underestimated in our study.

As mentioned earlier, diabetic patients with higher

fasting plasma glucose showed lower plasma insulin andC-peptide responses than those with lower fasting plasmaglucose. This is in accordance with the horseshoe-shapedinsulin-response curve at different levels of hypergly-cemia, originally described by Reaven and Miller (32).The low plasma insulin levels in hyperglycemic NIDDMpatients have been shown to be reversible independentof the mode of treatment of hyperglycemia (33).

Metabolic control of diabetes was mostly poor in ourpatients at the 5-yr examination, and many would havefulfilled the criteria for secondary failure. Laakso et al.(34) reported a similar degree of hyperglycemia to thatfound in this study in a large cross-sectional study con-ducted in East and West Finland including 1059 NIDDMpatients.

During the 1 yr after dignosis, most of our patientscould lose weight, and a marked improvement in met-abolic control was seen in those patients followed upby our department. At the 5-yr examination, the meansubscapular skin fold thickness was smaller than at base-line in diabetic patients, confirming the reduction in fatmass (6). However, patients were still overweight, andthe inability of most diabetic patients to achieve normalbody weight might explain why most were in poor met-abolic control. Because weight loss improves both in-sulin sensitivity and insulin secretion, more emphasisshould be put on dietary treatment and the need for anincrease in physical activity of obese NIDDM patients,particularly during the first years from the time of di-agnosis.

ACKNOWLEDGMENTS

We thank Eeva-Maija Oittinen for secretarial assistancein preparation of the manuscript.

This study was supported by grants from the Yrjo Jahns-son Foundation, the Finnish Foundation of Diabetes Re-search, Nordisk Insulinfond, Helena Vuorenmies Foun-dation, Orion Corporation Research Foundation, andthe North Savo Regional Fund of the Finnish CulturalFoundation.

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