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非胰島素依賴型糖尿病的臨床特徵是空腹血糖過高．它是冠狀動脈疾病危險因素之一
．中華民國台灣地區的流行率和盛行率愈來愈高．雖然非胰島素依賴型糖尿病的原因
迄今不明，但能瞭解葡萄糖的代謝管制，對以後的研究相當重要．這篇論文主要包含
三部份，其內容主要是：（１）於糖尿病鼠評估血中游離脂肪酸和肝臟產糖能力的關
係，（２）於非胰島素依賴型糖尿病患者身上，探討肝臟產糖能力（hepaticglucose
production , HGP）和葡萄糖利用率（Rate of glucose disposal,RD ）與空腹高血
壓的關係，（３）於非胰島素依賴型糖尿病患者身上評估第二代口服降糖藥
glipizide 對葡萄糖代謝的影響．
第一部份的實驗用streptozotocin (25 mg/kg) 誘發400-450公克Sprague-Dawley 鼠
成糖尿病後，評估菸鹼酸降低血糖的效果．菸鹼酸注射後，血中游離脂肪酸濃度和葡
萄糖濃度皆減少．對照組糖尿病鼠接受食鹽水注射，血中游離脂肪酸濃度和葡萄糖濃
度皆沒有改變．不拘注射菸鹼酸或食鹽水，血中胰島素濃度維持不變．肝臟產糖能力
以[3-3H]葡萄糖測量．注射菸鹼酸後，不僅葡萄糖濃度減少，肝臟產糖能力亦減少．
這些結果指出血中游離脂肪酸增加可能和高血糖有關．以菸鹼酸降血糖的效果與它抗
脂解作用有關，並藉減少肝臟產糖能力造成的．
第二個實驗觀察8位非胰島素依賴型糖尿病病患和6位正常人從晚上10時起至次日下午
2時肝臟產糖能力、葡萄糖利用率、葡萄糖濃度、和胰島素濃度的變化．在晚上10 點
時，非胰島素依賴型糖尿病患者之肝臟產糖能力比正常人高（4.73±0.61 v.s.
1.67±0.47 mg/kg/min,p>0.05 ）．糖尿病患者血中葡萄糖濃度也是隨時間進展而逐
漸下降，但至次日下午2時止，仍維持比正常人約3倍高的血糖值，即245±27 mg/dl
．非胰島素依賴型糖尿病患者血中胰島素濃度的全程變化亦隨時間進展而逐漸減少，
大部份的階段與正常人幾乎相同．因此，非胰島素依賴型糖尿病患肝臟產糖能力、血
中葡萄糖濃度、和血中胰島素濃度在此16小時觀察中，都是隨時間進展而逐漸減少．
葡萄糖利用率在非胰島素依賴型糖尿病患者和正常人身上亦逐漸減少，但糖尿病者下
降幅度大．因此葡萄糖利用率在晚上10點時，糖尿病患者比正常人高（3.97±0.4
v.s. 3.25±0.13 mg/kg/min, p<0.001 ）；在次日下午2點時，則比正常人低（1.64
± 0.21 v.s. 1.97±0.35 mg/kg/min, p<0.001）．這些結果顯示當肝臟產糖能力於
糖尿病者和正常人身上是相同時，糖尿病者仍有很高的葡萄糖濃度，所以空腹血糖的
高低不是單靠肝臟產糖能力一項因素就可決定的．
第三個實驗觀察 19 位非胰島素依賴型糖尿病患者接受第二代口服降糖藥 glipizide
2.5個月至6個月之後，各種代謝指標的變化．就全體而言，但由於病人對 glipizide
治療的反應不同，所以分為兩組加以分析．其中一組包含 9位平均空腹血糖下降達72
mg/dl 的病人（又叫”responders”），另外一組包含10位平均空腹血糖下降不及54
mg/dl的病人（又叫”nonresponders")．血糖控制較好的這一組，plipizide 治療後
增加了葡萄糖利用率和脂肪細胞的葡萄糖輸送率，同時血中游離脂肪酸濃度減少，基
礎肝臟產糖能力也減少．至於”non-resporders”這一組，除游離脂肪酸濃度外，其
餘三項於治療前後都沒有變化．另外，這兩組病人之血中胰島素濃度在治療後比治療
前略為增加，胰島素抑制肝臟製造葡萄糖的能力在治療前後則沒有差別．這些結果證
實glipizide確有改善葡萄糖代謝的功能,但臨床上每人反應的差異性極大．其次這個
實驗顯示 glipizide降血糖的作用是經由增加葡萄糖的利用率，減少血中游離脂肪酸
濃度，和減少基礎肝臟產糖能力而達成的．
非胰島素依賴型糖尿病空腹血糖的高低，與血中游離脂肪酸濃度、基礎肝臟產糖能力
和葡萄糖利用率有關．以口服降糖藥 glipizide治療，會增加葡萄糖利用率和葡萄糖
輸送率，減少血中游離脂肪酸濃度和基礎肝臟產糖能力、而使血中葡萄糖濃度減少．
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Non-insulin-dependent diabetes mellitus (NIDDM) is characterized by
fasting hyperglycemia, and is one of the major risk factor for coronary
artery disease (CAD). The incidence and prevalence in this country is
growing rapidly. Although the etiology of NIDDM remains unclear, it is
noteworthy to understand the underlying regulation of glucose metabolism
in patients with NIDDM. This thesis consists of three parts. and the aim
of this thesis is to (1) assess the relationship between plasma free fatty
acid (FFA) and hepatic glucose production (HGP) in diabetic rats. (2)
investigate the interaction of basal HGP and tissue glucose disposal with
fasting hyperglycemia in patients with NIDDM, (3) evaluate the effect of
glipizide - - a second generation sulfonylurea (SU) compound - - on the
glucose metabolism in patients with NIDDM.
The study in part one is to evaluate the ability of nicotinic acid (NA), a
potent antilipolytic agent, to lower plasma glucose concentration in
400-450g male diabetic rats. Diabetes was induced by intravenous
streptozotocin (STZ, 25 mg/kg) injection, and the rats were studied 7-10
days later. Mean (±SEM) fasting glucose concentration decreased 4 hafter
subcutaneous injection of NA at 0 and 2 H. The decrease of plasma glucose
concentration was associated with a sustained fall of plasma FFA
concentrations. With injection of normal saline (NaC1) neither plasma
glucose nor FFA concentratio ns decreased in diabetic rats. There was
nochange in the plasma insulin concentration in response to NA or normal
saline injection. Hepatic glucose production was quantified by performing
glucose turnover studies with [3-3H] glucose, and the decrease in plasma
glucose produced by NA in diabetic rats was associated with a reduction in
HGP. These data are consistent with the view that elevated plasma FFA
concentrations contribute to hyperglycemia in rats with STZ-induced
diabetes and that the hypoglycemic efficacy of NA may be related to its
antilipolytic effect, possibly mediated by reducing HGP.
In the following study, the changes in basal HGP, tissue glucose disposal,
and plasma glucose and insulin concentration that took place over a 16-h
period from 10 to 2 p.m. were documented in 14 individuals; 8 with NIDDM
and 6 with normal glucose tolerance. Values of basal HGP were higher than
normal in patients with NIDDM at 10 p.m.(4.73 ± 0.41 v.s. 3.51 ± 0.36
mg/kg/min, p < 0.001), but feell at a much faster rate throughout the
night than that seen in normal subjects. As a consequence, the difference
between basal HGP in normal individuals and patients with NIDDM
progressively norrowed, and by 2 p.m., had ceased to exist (1.75 ± 0.61
v.s. 1.67 ± 0.47 mg/Kg/min, p> 0.05). Plasma glucose concentration also
declined in patients with NIDDM over the same period of time, but they
remained quite hyperglycemic, and the value 245 ± 27 mg/dl at 2 p.m. was
about three times greater than in normal individuals. Plasma insulin
concentrations also fell progressively from 10 to 2 p.m., and were similar
in both groups throughout most of the 16-h study peroid. Thus, the
progressive decline in basal HGP in patients with NIDDM occurred despite
concomitant fall in both plasma glucose and insulin concentration. Glucose
disposal rate also fell progressively in both groups, but the magnitude of
the fall was greater in patients with NIDDM. Consequently, the rate of
glucose disposal in patients with NIDDM was higher at 10 p.m. (3.97 ±
0.48 v.s. 3.25 ± 0.13 mg/Kg/min, p < 0.001) and lower the following day
at 2 p.m. (1.64 ± 0.21 v.s. 1.97 ± 0.35 mg/Kg/min, p< 0.01). These
results indicate that a greatly expanded pool size can exist in patients
with NIDDM at a time when values for basal HGP are identical to those in
normal subjects studied under comparable conditions, which suggests that
fasting hyperglycemia in NIDDM is not simply a funcion of and increase in
basal hGP.
The third study was subjected to evaluate the effect of glipizide
treatment on glucose metabolism. Nineteen patients with NIDDM were treated
with glipizide for 2.5 to 6 months. Glycemic control was significantly
improved in the group as a whole, but considerable variability was seen.
Therefore, two groups were created for further data analysis, consisting
of g patients whose fasting plasma glucose concentrations decreased by 72
mg/dl ("responders"), and 10 patients in whom the fall in fasting plasma
glucose concentration was 54 mg/dl or less ("non-responders"). Patients
with the best glycemic response were shown to have an increase in glucose
metabolic clearance rate (MCR), estimated in vivo by glucose clamp
studies, and glucose transport rate, estimated in vitro by using isolated
adipocytes. Patients with the best glycemic response also had significant
decrease in both ambient plasma FFA concentration and basal HGP following
glipizide treatment. In contrast, all of these variables were unchanged in
those patients with the least glycemic response to glipizide. On the other
hand, plasma insulin concentrations increased to a similar degree in both
groups after glipizide treatment. Furthermore, the ability of insuling to
inhibit HGP was also comparable in those with the best as compared to
those with the worst glycemic response to glipizide. These data confirm
that glycemic control improves in association with glipizide treatment in
patinets with NIDDM, and emphasize the variability in the magnitude of the
therapeutic response. Furthermore, they raise the possibility that the
ability of glipizide to lower plasma glucose concentration in patinets
with NIDDM is secondary to increase glucose MCR and decrease in
circulating plasma FFA concentration and basal HGP.
In conclusion, the magnitude of fasting plasma glucose concentration has a
strong relationship with plasma FFA concentration, basal HGP, and glucose
disposal rate, The hypoglycemic effect of glipizide is associated with
increase in glucose MCR and in vitro glucose transport, and decrease in
plasma FFA concnetration and basal HGP.
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